Lighting up the tumor fire with low-dose irradiation

Abstract

Low T cell infiltration of tumors is a dominant feature of advanced cancer patients who do not respond to immune checkpoint inhibitors.Numerous efforts to promote antitumor immune responses by combining high-dose tumor-targeted radiation to a few tumor deposits with immune checkpoint blockade have been attempted to induce immune-mediated systemic tumor regression. However, abscopal effects are uncommon in cancer patients, and high-dose irradiation of large tumor volumes is curtailed by potential local and systemic toxicity.In mouse and human studies, three recent publications demonstrate the ability of low-dose radiation directed at large metastatic deposits to enhance immunotherapy by reprogramming the tumor microenvironment, facilitating T cell priming via innate immune stimulation in the lymph node, increasing the frequency of tumor-specific T cells, and modulating the immune suppressive stroma in favor of tumor eradication.These findings pave the way for the clinical development of innovative and effective combinatorial radioimmunotherapies. Current efforts combining immunotherapy and radiation have focused on high-dose radiation delivered to few tumor lesions, aiming to generate diffuse abscopal effects; however, these effects are uncommon in patients. Three recent studies in mouse tumor models and human cancer patients show that low-dose radiation (LDRT) delivered to all tumor lesions effectively mobilizes innate and adaptive immunity and synergizes with immunotherapy. These new findings suggest LDRT’s potential as an immune amplifier capable of reprogramming the tumor microenvironment, instigating inflammation, and sensitizing 'cold' tumors to immune checkpoint blockade responsiveness. Current efforts combining immunotherapy and radiation have focused on high-dose radiation delivered to few tumor lesions, aiming to generate diffuse abscopal effects; however, these effects are uncommon in patients. Three recent studies in mouse tumor models and human cancer patients show that low-dose radiation (LDRT) delivered to all tumor lesions effectively mobilizes innate and adaptive immunity and synergizes with immunotherapy. These new findings suggest LDRT’s potential as an immune amplifier capable of reprogramming the tumor microenvironment, instigating inflammation, and sensitizing 'cold' tumors to immune checkpoint blockade responsiveness. Cancer treatment has been transformed by the introduction of immune checkpoint inhibitors (see Glossary) that target negative regulators of T cell function, such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) and its ligand (PD-L1). However, less than 50% of patients are eligible for immune checkpoint blockade (ICB) therapies and less than 50% of these will benefit [1.Haslam A. Prasad V. Estimation of the percentage of US patients with cancer who are eligible for and respond to checkpoint inhibitor immunotherapy drugs.JAMA Netw. Open. 2019; 2e192535Crossref PubMed Scopus (365) Google Scholar]. Low tumor mutation burden (TMB) and low T cell infiltration, for example, are associated with low responses to various ICBs [2.Ochoa de Olza M. et al.Turning up the heat on non-immunoreactive tumours: opportunities for clinical development.Lancet Oncol. 2020; 21: e419-e430Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar,3.Tumeh P.C. et al.PD-1 blockade induces responses by inhibiting adaptive immune resistance.Nature. 2014; 515: 568-571Crossref PubMed Scopus (3972) Google Scholar], while the frequency of CD8+PD-1high tumor-infiltrating lymphocytes (TILs) may predict therapy response [4.Thommen D.S. et al.A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade.Nat. Med. 2018; 24: 994-1004Crossref PubMed Scopus (435) Google Scholar]. Similarly, a subset of TILs known as precursor exhausted CD8+ T cells sustain the tumor response to ICB [5.Im S.J. et al.Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy.Nature. 2016; 537: 417-421Crossref PubMed Scopus (796) Google Scholar, 6.Miller B.C. et al.Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade.Nat. Immunol. 2019; 20: 326-336Crossref PubMed Scopus (500) Google Scholar, 7.Kallies A. et al.Precursor exhausted T cells: key to successful immunotherapy?.Nat. Rev. Immunol. 2020; 20: 128-136Crossref PubMed Scopus (104) Google Scholar, 8.Siddiqui I. et al.Intratumoral Tcf1+PD-1+CD8+ T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy.Immunity. 2019; 50: 195-211.e110Abstract Full Text Full Text PDF PubMed Scopus (431) Google Scholar, 9.Chu T. Zehn D. Charting the roadmap of T cell exhaustion.Immunity. 2020; 52: 724-726Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar]. Furthermore, T cell clonal expansion in peripheral blood or in tumor samples has been associated with durable responses to ICB therapy [10.Fairfax B.P. et al.Peripheral CD8+ T cell characteristics associated with durable responses to immune checkpoint blockade in patients with metastatic melanoma.Nat. Med. 2020; 26: 193-199Crossref PubMed Scopus (92) Google Scholar]. Thus, pre-existing immunity can help to predict responses to ICB; however, only a fraction of tumors is infiltrated by relevant T cells at the steady state. A key goal of cancer immunotherapy remains to overcome tumor primary resistance by promoting T cell infiltration of 'cold' tumors. To promote antitumor immune responses, to date, many efforts have focused on combinations of high-dose external-beam irradiation (EBRT) to a few tumor deposits (e.g., >5 Gy per fraction; oligoRT) and immunotherapy. Essentially, irradiation is meant to trigger an in situ tumor vaccination effect, inducing systemic immunity and the so-called abscopal effect, which refers to the immune-mediated destruction of metastatic lesions in distant non-irradiated organs [11.Herrera F.G. et al.Radiotherapy combination opportunities leveraging immunity for the next oncology practice.CA Cancer J. Clin. 2017; 67: 65-85Crossref PubMed Scopus (221) Google Scholar]. However, clinical emerging evidence in randomized studies testing oligoRT combinations with ICB suggests that such abscopal effects may be rare [12.McBride S. et al.Randomized Phase II trial of nivolumab with stereotactic body radiotherapy versus nivolumab alone in metastatic head and neck squamous cell carcinoma.J. Clin. Oncol. 2021; 39: 30-37Crossref PubMed Scopus (82) Google Scholar]. The expectation that oligoRT to one lesion would change the tumor microenvironment (TME) in distant lesions may be unrealistic, because the latter is determined by local interactions between the host and tumor cells, guided by the local genetic background and molecular states of the latter [13.Wellenstein M.D. de Visser K.E. Cancer-cell-intrinsic mechanisms shaping the tumor immune landscape.Immunity. 2018; 48: 399-416Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar,14.Dentro S.C. et al.Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes.Cell. 2021; 184: 2239-2254.e2239Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar]. Although oligoRT may induce in situ vaccination, decades of cancer vaccine failures [15.Rosenberg S.A. et al.Cancer immunotherapy: moving beyond current vaccines.Nat. Med. 2004; 10: 909-915Crossref PubMed Scopus (2443) Google Scholar] demonstrate that, in addition to eliciting a systemic immune response, local reprogramming of the TME in all distant lesions is required (Figure 1, Key figure ). The inherent toxicity and immune suppression resulting from high-dose radiation directed at many tumor deposits precludes the use of oligoRT in this context. Three new studies, however, illustrate the feasibility of low-dose radiotherapy (LDRT) (e.g., doses below 3 Gy) directed at large metastatic deposits to stimulate innate and adaptive immunity, which we posit may be a promising anticancer therapeutic strategy moving forward. In the first study [16.Patel R.B. et al.Low-dose targeted radionuclide therapy renders immunologically cold tumors responsive to immune checkpoint blockade.Sci. Transl. Med. 2021; eabb3631Crossref PubMed Google Scholar], targeted radionuclide therapy (TRT) using 90Y-NM600 was shown to render immunologically cold syngeneic B78 melanoma tumors sensitive to ICB therapy. After low-dose TRT, a significant increase in tumor-infiltrating myeloid (CD11b+) and natural killer (NK) cells, as well as an increase in the ratio of effector CD8+ to suppressor CD4+CD25+FOXP3+ T regulatory (Treg) cells, was observed compared to controls, along with improved responses to ICB. The radionuclide 90Y-NM600 is a theranostic alkylphosphocholine radiometal chelate that binds preferentially to tumors and can be used for cancer therapy via β-particle-emitting 90Y-NM600 [16.Patel R.B. et al.Low-dose targeted radionuclide therapy renders immunologically cold tumors responsive to immune checkpoint blockade.Sci. Transl. Med. 2021; eabb3631Crossref PubMed Google Scholar], delivering radiation to the TME within a path length of 3.9 mm. The dose is absorbed almost entirely in the tumor, without significant exposure of the bone marrow, spleen, or draining lymph nodes (dLNs). A study looking at the biodistribution, tumor selectivity, and safety of 90Y-NM600 in several preclinical syngeneic or xenograft mouse tumor models (including melanoma and lymphoma as well as lung, pancreatic, prostate, and colon adenocarcinomas) has shown that 90Y-NM600 is safe and suitable for human applications [17.Grudzinski J.J. et al.Preclinical characterization of 86/90Y-NM600 in a variety of murine and human cancer tumor models.J. Nucl. Med. 2019; 60: 1622-1628Crossref PubMed Scopus (9) Google Scholar], with clinical studies under way. This work in B78 melanoma [16.Patel R.B. et al.Low-dose targeted radionuclide therapy renders immunologically cold tumors responsive to immune checkpoint blockade.Sci. Transl. Med. 2021; eabb3631Crossref PubMed Google Scholar] revealed that low 90Y-NM600 doses delivering 2.5 Gy to tumors produced important immune reprogramming of the TME. It upregulated type I interferon (IFN) signatures, which were dependent on cGMP-AMP (cGAMP) synthase (cGAS)/stimulator of interferon genes (STING), as evidenced by activation of the pathway post-irradiation and by the loss of the therapeutic activity in a STING knockout (Tmem173−/-) B16 melanoma mouse tumor; the treatment also resulted in reprogrammed immune and endothelial cells, as evidenced by high-dimensional phenotypic flow cytometry and transcriptomic analyses [16.Patel R.B. et al.Low-dose targeted radionuclide therapy renders immunologically cold tumors responsive to immune checkpoint blockade.Sci. Transl. Med. 2021; eabb3631Crossref PubMed Google Scholar]. Consistent with a radionuclide half-life of 2.5 days, these changes were short lived and returned to baseline by day 14. However, when combined with CTLA-4 monoclonal antibody (mAb) blockade in the same mouse model, TRT led to increased total CD8+ as well tissue-resident memory T cells and innate γδ T cells, while CD8+ T cells exhibited more clonal expansion and less phenotypic and functional exhaustion than either treatment alone, as shown via flow cytometry and T cell receptor (TCR) sequencing [16.Patel R.B. et al.Low-dose targeted radionuclide therapy renders immunologically cold tumors responsive to immune checkpoint blockade.Sci. Transl. Med. 2021; eabb3631Crossref PubMed Google Scholar]. The combination of TRT with ICB significantly improved the survival of treated mice compared to either treatment alone. Furthermore, the co-administration of oligoRT (12 Gy to one lesion) and 90Y-NM600 together with anti-CTLA-4 mAb blockade further enhanced the therapeutic efficacy and induced more abscopal effects compared to either treatment alone. In addition, mice that achieved long-term tumor clearance after combinatorial therapy developed protective immune memory [16.Patel R.B. et al.Low-dose targeted radionuclide therapy renders immunologically cold tumors responsive to immune checkpoint blockade.Sci. Transl. Med. 2021; eabb3631Crossref PubMed Google Scholar]. Hence, low-dose 90Y-NM600 and oligoRT were reported to be complementary in their ability to augment the response to ICBs. Overall, this study indicated that low-dose TRT could reprogram the TME and convert cold tumors into immunoreactive and ICB-responsive ones. These findings provide the foundations for clinical testing of the sequence of TRT in combination with immune checkpoint inhibitors to treat cold tumors. In a second study, our research group investigated the use of LDRT in the syngeneic ID8 ovarian cancer mouse model [18.Herrera F.G. et al.Low-dose radiotherapy reverses tumor immune desertification and resistance to immunotherapy.Cancer Discov. 2021; 12: 108-133Crossref PubMed Scopus (13) Google Scholar] mimicking the low T cell infiltration seen in many human epithelial ovarian carcinomas [19.Zhang L. et al.Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer.N. Engl. J. Med. 2003; 348: 203-213Crossref PubMed Scopus (2482) Google Scholar] which are naturally resistant to ICB. We found that external-beam whole-abdominal irradiation at 0.5–2 Gy could inflame cold tumors by increasing the frequency of lymphocytes, monocytes, dendritic cells (DCs), and NK cells in the TME, with 1-Gy irradiation resulting in the greatest immune cell infiltration and the highest CD8+ T:Treg cell ratio. This was relevant because, to our knowledge, this was the first time that EBRT was administered at low doses to large abdominal volumes without causing toxicity, with the goal of reprogramming the TME and promoting immune cell infiltration rather than causing tumor cell The effects were T cell after 1 However, 1-Gy resulted in immune cell into ovarian tumors. we immune upregulated within tumors by LDRT on day genes the T cell PD-1 and CTLA-4 by exhausted the of cells and a key receptor in myeloid These findings the of combinatorial therapy ICB to effector T cells, along with ligand to cells, and low-dose to A of immunotherapy LDRT Gy to the inhibiting PD-1 and an antibody and low-dose resulted in an tumor response and a in this model, which was to the immunotherapy combination alone. without one of the and characterization of the immune TME revealed that all of the were required for survival benefit innate and adaptive immunity activation was required for cancer [18.Herrera F.G. et al.Low-dose radiotherapy reverses tumor immune desertification and resistance to immunotherapy.Cancer Discov. 2021; 12: 108-133Crossref PubMed Scopus (13) Google Scholar]. was associated with an of TILs and CD8+ effector T cells with of and also induced a new of type and the NK group ligand et of human and mouse lung myeloid across and 2019; 50: Full Text Full Text PDF PubMed Scopus Google Scholar]. in tumors and CD8+ TILs with an exhausted upregulated the This was relevant as these TILs a subset of exhausted T cells with effector and proliferative In of a of the therapeutic of was by antibody Furthermore, inhibiting T cell from with also as evidenced by a of survival and indicated that effector cells were to tumors from lymph nodes [18.Herrera F.G. et al.Low-dose radiotherapy reverses tumor immune desertification and resistance to immunotherapy.Cancer Discov. 2021; 12: 108-133Crossref PubMed Scopus (13) Google Scholar]. This that of in was required to the pool of effector A Phase I clinical trial the findings [18.Herrera F.G. et al.Low-dose radiotherapy reverses tumor immune desertification and resistance to immunotherapy.Cancer Discov. 2021; 12: 108-133Crossref PubMed Scopus (13) Google patients with metastatic prostate, or colon tumors were as with a of than CD8+ T cells per were treated with a combination of LDRT or 1 Gy per fraction total dose or low-dose and The combination resulted in of lesions in three patients on or with an in response of while patients achieved control responses and and one The of was and new safety to mouse led to in and CD8+ T cells as well as T to tumor in responsive as evidenced by tumors in the tumor as evidenced by immune the key of delivered patients of all was observed only in lesions the [18.Herrera F.G. et al.Low-dose radiotherapy reverses tumor immune desertification and resistance to immunotherapy.Cancer Discov. 2021; 12: 108-133Crossref PubMed Scopus (13) Google Scholar]. These findings that the observed between LDRT and immunotherapy was not to a systemic abscopal rather to the local effects by the of the the TME was by LDRT to tumor control by immune cells, the mechanisms of this in patients to be further this study the systemic of T cell immunity in peripheral blood via sequencing of blood lymphocytes significant changes in the T cell which was not in lesions to LDRT and which tumor [18.Herrera F.G. et al.Low-dose radiotherapy reverses tumor immune desertification and resistance to immunotherapy.Cancer Discov. 2021; 12: 108-133Crossref PubMed Scopus (13) Google Scholar]. These studies in human and mouse have shown that LDRT can be delivered large tumor volumes to reprogram cold of and responses to immunotherapy. A study et al.Low-dose radiation treatment systemic antitumor immune responses by the 2020; PubMed Scopus Google Scholar] the combination of oligoRT to a metastatic lesion together with LDRT 1-Gy to and ICB in a murine lung tumor model in irradiation and of in the TME of metastatic lesions, systemic tumor when combined with oligoRT and therapy et al.Low-dose radiation treatment systemic antitumor immune responses by the 2020; PubMed Scopus Google Scholar]. of metastatic tumors was by the of innate and adaptive immunity, and CD8+ T cells, as evidenced by a significant increase in their using flow In a Phase I clinical study patients with tumors to squamous cell of the head and cell and were treated by a combination of while antibody therapy was to on the The combination was found to be safe and of patients a response of a with squamous cell was oligoRT to a lung lesion and LDRT to abdominal lesions while mAb therapy was A response was observed the lesions were in A was in a with advanced melanoma et al.Low-dose radiation treatment systemic antitumor immune responses by the 2020; PubMed Scopus Google Scholar]. The preclinical and clinical in this study suggest that LDRT delivered to metastatic lesions the abscopal in and to date, to trigger via oligoRT delivered to a lesion in combination with ICB. These that such effects be achieved in cancer patients. We that these findings research development of in patients who were to ICB. The study also the effects of external-beam LDRT in reprogramming the TME, which in this model, also These studies [16.Patel R.B. et al.Low-dose targeted radionuclide therapy renders immunologically cold tumors responsive to immune checkpoint blockade.Sci. Transl. Med. 2021; eabb3631Crossref PubMed Google F.G. et al.Low-dose radiotherapy reverses tumor immune desertification and resistance to immunotherapy.Cancer Discov. 2021; 12: 108-133Crossref PubMed Scopus (13) Google et al.Low-dose radiation treatment systemic antitumor immune responses by the 2020; PubMed Scopus Google Scholar] provide important preclinical and clinical a in the irradiation of metastatic on work that myeloid and T cell infiltration in murine tumors could an tumor and T cell and antitumor responses T cell et al.Low-dose irradiation to an that effective T cell immunotherapy.Cancer 24: Full Text Full Text PDF PubMed Scopus Google Scholar]. We that low doses delivered to all tumors using EBRT or systemic TRT, to effectively innate and adaptive immunity cold tumors while also immune suppressive and are for combination with ICB (Figure Furthermore, as the first and studies show [16.Patel R.B. et al.Low-dose targeted radionuclide therapy renders immunologically cold tumors responsive to immune checkpoint blockade.Sci. Transl. Med. 2021; eabb3631Crossref PubMed Google et al.Low-dose radiation treatment systemic antitumor immune responses by the 2020; PubMed Scopus Google Scholar], oligoRT can be combined with diffuse low-dose EBRT or systemic TRT to trigger in situ vaccination the while cold tumor lesions may be reprogrammed the the rare abscopal effects of The of LDRT could be by the tumor type and tumors of can be effectively treated by low-dose the of TRT is that is can to all metastatic deposits of are by which is a of research will to such to this response by the of therapeutic will be to (e.g., et and survival in metastatic cancer.N. Engl. J. Med. PubMed Scopus Google or et for metastatic cancer.N. Engl. J. Med. 2021; PubMed Scopus Google Scholar] that are in clinical use can induce the same when delivered at low doses in combination with as well as in combination with of immune resistance mechanisms to reported high-dose oligoRT also in response to low-dose TRT and ICB will also be of key et microenvironment after mechanisms of resistance and Rev. PubMed Scopus Google Scholar, et is a of radiation antitumor PubMed Scopus Google Scholar, et of synergizes with radiotherapy by reprogramming the tumor microenvironment to overcome immune 2021; 39: Full Text Full Text PDF PubMed Scopus Google Scholar]. work is required to immunologically doses and of radiation as well as the of a required that the effects are (see studies will also to combinations that benefit from the addition of Furthermore, are properties immune desertification that also resistance to radiation remains an low-dose irradiation (LDRT) is LDRT can be used to treat metastatic lesions that are on However, therapeutic would be in the treatment of systemic research be to the effective of irradiation for a clinical is the dose and for The studies doses from to 2.5 Gy administered or three at work is to the immunologically radiation dose and as well as the of which are required to the of the mechanisms are in response to oligoRT induces a response by inflammation, of the and of all of which may to tumor studies LDRT in combination with immune checkpoint blockade (ICB) can induce the same type of immune suppression that be in the TME to more tumor responses to combinations benefit from the addition of A for research is precursor exhausted T cells can be further with immune checkpoint inhibitors to their effector or new the innate and adaptive immune can in the of less effector survival and increasing tumor that to immune desertification and resistance to ICB also to resistance to LDRT and combinatorial in the or as well as in or of the can T cell and in a TME for tumors. Thus, the of such mechanisms also resistance to LDRT in combination with immunotherapy remains low-dose irradiation (LDRT) is LDRT can be used to treat metastatic lesions that are on However, therapeutic would be in the treatment of systemic research be to the effective of irradiation for a clinical is the dose and for The studies doses from to 2.5 Gy administered or three at work is to the immunologically radiation dose and as well as the of which are required to the of the mechanisms are in response to oligoRT induces a response by inflammation, of the and of all of which may to tumor studies LDRT in combination with immune checkpoint blockade (ICB) can induce the same type of immune suppression that be in the TME to more tumor responses to immunotherapy. combinations benefit from the addition of A for research is precursor exhausted T cells can be further with immune checkpoint inhibitors to their effector or new the innate and adaptive immune can in the of less effector survival and increasing tumor that to immune desertification and resistance to ICB also to resistance to LDRT and combinatorial in the or as well as in or of the can T cell and in a TME for tumors. Thus, the of such mechanisms also resistance to LDRT in combination with immunotherapy remains This work was by the for Cancer and from the Cancer and the and are with to cancer with increased the of the for of refers to tumor observed the of key cells for CD8+ T cell is dependent on the and that binds to as well as and tumor on the or of T cells in the TME. tumors are of T cells or immune to T cell infiltration of tumors T cell priming and T cell to tumor checkpoint inhibitors are not effective in therapeutic strategy on the of T immune checkpoint that and are by cancer to immune the immune checkpoint developed for the use of in in cancer immunotherapy when tumors in cancer patients the same or mAb that binds CTLA-4 and its with and It negative on T first immunotherapy in melanoma in therapy cells and the microenvironment with human monoclonal antibody that a negative that effector CD8+ T second immunotherapy by the for the treatment of a of tumor high-dose irradiation delivered to a few to tumor CD8+ T cell on by the of which a subset associated with effective immunity and by radiation per in 1 Gy 1 is a radiotherapy that and with in of increased bone such as bone protein in the by produced by and by of STING type I and

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