Inhibitor of glutamine metabolism V9302 promotes ROS-induced autophagic degradation of B7H3 to enhance antitumor immunity

Abstract

Despite the enormous successes of anti-PD-1/PD-L1 immunotherapy in multiple other cancer types, the overall response rates of breast cancer remain suboptimal. Therefore, exploring additional immune checkpoint molecules for potential cancer treatment is crucial. B7H3, a T-cell coinhibitory molecule, is specifically overexpressed in breast cancer compared with normal breast tissue and benign lesions, making it an attractive therapeutic target. However, the mechanism by which B7H3 contributes to the cancer phenotype is unclear. Here we show that the expression of B7H3 is negatively related to the number of CD8+ T cells in breast tumor sites. In addition, analysis of the differentially expressed B7H3 reveals that it is inversely correlated to autophagic flux both in breast cancer cell lines and clinical tumor tissues. Furthermore, block of autophagy by bafilomycin A1 (Baf A1) increases B7H3 levels and attenuates CD8+ T cell activation, while promotion of autophagy by V9302, a small-molecule inhibitor of glutamine metabolism, decreases B7H3 expression and enhances granzyme B (GzB) production of CD8+ T cells via regulation of reactive oxygen species (ROS) accumulation. We demonstrate that combined treatment with V9302 and anti-PD-1 monoclonal antibody (mAb) enhances antitumor immunity in syngeneic mouse models. Collectively, our findings unveil the beneficial effect of V9302 in boosting antitumor immune response in breast cancer and illustrate that anti-PD-1 together with V9302 treatment may provide synergistic effects in the treatment of patients insensitive to anti-PD-1 therapy. Despite the enormous successes of anti-PD-1/PD-L1 immunotherapy in multiple other cancer types, the overall response rates of breast cancer remain suboptimal. Therefore, exploring additional immune checkpoint molecules for potential cancer treatment is crucial. B7H3, a T-cell coinhibitory molecule, is specifically overexpressed in breast cancer compared with normal breast tissue and benign lesions, making it an attractive therapeutic target. However, the mechanism by which B7H3 contributes to the cancer phenotype is unclear. Here we show that the expression of B7H3 is negatively related to the number of CD8+ T cells in breast tumor sites. In addition, analysis of the differentially expressed B7H3 reveals that it is inversely correlated to autophagic flux both in breast cancer cell lines and clinical tumor tissues. Furthermore, block of autophagy by bafilomycin A1 (Baf A1) increases B7H3 levels and attenuates CD8+ T cell activation, while promotion of autophagy by V9302, a small-molecule inhibitor of glutamine metabolism, decreases B7H3 expression and enhances granzyme B (GzB) production of CD8+ T cells via regulation of reactive oxygen species (ROS) accumulation. We demonstrate that combined treatment with V9302 and anti-PD-1 monoclonal antibody (mAb) enhances antitumor immunity in syngeneic mouse models. Collectively, our findings unveil the beneficial effect of V9302 in boosting antitumor immune response in breast cancer and illustrate that anti-PD-1 together with V9302 treatment may provide synergistic effects in the treatment of patients insensitive to anti-PD-1 therapy. Breast cancer is reported as the most commonly diagnosed cancer and the leading cause of cancer death in women based on Global Cancer Statistics 2020 (1Sung H. Ferlay J. Siegel R.L. Laversanne M. Soerjomataram I. Jemal A. Bray F. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J. Clin. 2021; 71: 209-249Crossref PubMed Scopus (10063) Google Scholar). Patients’ survival was dramatically improved over the past 10 years, as available treatment modalities optimized, including surgery, radiotherapy, chemotherapy, endocrine therapy, targeted biological therapy, and immunotherapy. With the clinical success of immune checkpoint inhibitors in some cancer types, immunotherapy has now undergone a paradigm transition from “immune enhancement” strategy to “immune normalization” strategy. The enhancement strategy focuses on enhancing antitumor immune response by using IL-2, interferons (IFNs), and CAR-T cells. Normalization treatment strategy suggests removing tumor-induced immune-inhibitory molecules that inhibit antitumor immunity including PD-1, PD-L1, CTLA-4, etc. Despite immunotherapy, employing anti-PD-1/PD-L1 has been widespreadly utilized in multiple malignant tumors (2Sanmamed M.F. Chen L. A paradigm shift in cancer immunotherapy: From enhancement to normalization.Cell. 2018; 175: 313-326Abstract Full Text Full Text PDF PubMed Scopus (530) Google Scholar), clinical trials evaluating monotherapy of anti-PD-1/PD-L1 for patients with early-phase breast cancer showed marginal effect with the objective response rate (ORR) ranging from 5.2 to 18.5% (3Dirix L.Y. Takacs I. Jerusalem G. Nikolinakos P. Arkenau H.T. Forero-Torres A. Boccia R. Lippman M.E. Somer R. Smakal M. Emens L.A. Hrinczenko B. Edenfield W. Gurtler J. von Heydebreck A. et al.Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: A phase 1b JAVELIN solid tumor study.Breast Cancer Res. Treat. 2018; 167: 671-686Crossref PubMed Scopus (349) Google Scholar, 4Emens L.A. Cruz C. Eder J.P. Braiteh F. Chung C. Tolaney S.M. Kuter I. Nanda R. Cassier P.A. Delord J.P. Gordon M.S. ElGabry E. Chang C.W. Sarkar I. Grossman W. et al.Long-term clinical outcomes and biomarker analyses of atezolizumab therapy for patients with metastatic triple-negative breast cancer: A phase 1 study.JAMA Oncol. 2019; 5: 74-82Crossref PubMed Scopus (335) Google Scholar, 5Nanda R. Chow L.Q. Dees E.C. Berger R. Gupta S. Geva R. Pusztai L. Pathiraja K. Aktan G. Cheng J.D. Karantza V. Buisseret L. Pembrolizumab in patients with advanced triple-negative breast cancer: Phase ib KEYNOTE-012 study.J. Clin. Oncol. 2016; 34: 2460-2467Crossref PubMed Scopus (870) Google Scholar, 6Rugo H.S. Delord J.P. Im S.A. Ott P.A. Piha-Paul S.A. Bedard P.L. Sachdev J. Le Tourneau C. van Brummelen E.M.J. Varga A. Salgado R. Loi S. Saraf S. Pietrangelo D. Karantza V. et al.Safety and antitumor activity of pembrolizumab in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer.Clin. Cancer Res. 2018; 24: 2804-2811Crossref PubMed Scopus (168) Google Scholar). Though the following trials adding the anti-PD-1/PD-L1 mAb to chemotherapy demonstrated improved response rate among a small subset of triple-negative breast cancer patients P. H.S. S. A. H. V. V. L. V. A. Loi S. Emens L.A. et as treatment for locally advanced or metastatic triple-negative breast cancer from a phase Oncol. Full Text Full Text PDF PubMed Scopus Google Scholar, P. J. Pusztai L. H. S. J. C. R. M. P.A. F. M. et for triple-negative breast J. PubMed Scopus Google Scholar), JAVELIN (3Dirix L.Y. Takacs I. Jerusalem G. Nikolinakos P. Arkenau H.T. Forero-Torres A. Boccia R. Lippman M.E. Somer R. Smakal M. Emens L.A. Hrinczenko B. Edenfield W. Gurtler J. von Heydebreck A. et al.Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: A phase 1b JAVELIN solid tumor study.Breast Cancer Res. Treat. 2018; 167: 671-686Crossref PubMed Scopus (349) Google showed was and H.S. Delord J.P. Im S.A. Ott P.A. Piha-Paul S.A. Bedard P.L. Sachdev J. Le Tourneau C. van Brummelen E.M.J. Varga A. Salgado R. Loi S. Saraf S. Pietrangelo D. Karantza V. et al.Safety and antitumor activity of pembrolizumab in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer.Clin. Cancer Res. 2018; 24: 2804-2811Crossref PubMed Scopus (168) Google in an of in estrogen receptor breast cancer the of breast cancer and to was to the tumor to of cells as cells T cells and on D. T 2021; PubMed Scopus Google Scholar, S. M. and 2021; Full Text Full Text PDF PubMed Scopus Google Scholar), and of other immune as B7H3, CTLA-4, P. S. A. and to cancer Full Text Full Text PDF PubMed Scopus Google Scholar). as is a cell which is expressed in and in normal tissues. B7H3 was related to advanced tumor and in multiple cancer and in tumor and G. S. Chen J. L. D. B7H3 expression enhances cell of via the Res. PubMed Scopus Google Scholar, B. S. A. of B7H3 expression in PubMed Scopus Google Scholar, J. the and of cell cells by Res. 2019; PubMed Scopus Google Scholar, S. S. K. C. H. L. S. D. et of tumors of tumor cells and tumor Full Text Full Text PDF PubMed Scopus Google Scholar). In to B7H3 is an of of was reported as an immune and now is to as an immune checkpoint to immune S. W. a checkpoint molecule, as a for cancer J. PubMed Scopus Google Scholar). was reported that B7H3 or CD8+ and tumor with showed a effect monotherapy K. K. S. H. R. K. H. M. S. K. et negatively cancer Cancer Res. 2018; 24: PubMed Scopus Google Scholar). Therefore, B7H3 is as a tumor immunotherapy for patients insensitive to anti-PD-1/PD-L1 therapy. glutamine is a of of cancer as and cancer H. K. S. D. and clinical of in Res. 2021; PubMed Scopus Google and is to to survival in breast cancer S. M. M. A. D. V. C. S. J. J. E. C. et of breast cancer and as Cancer Res. PubMed Scopus Google Scholar, R. L. D. M. The combined expression of is with a in breast Cancer Res. Treat. 2019; 175: PubMed Scopus Google Scholar). and to and is the for the in both tumor cell van M. D. L. S. M. R. C. et glutamine cancer growth and PubMed Scopus Google and T cell W. G. J. B. G. in T-cell and PubMed Scopus Google Scholar). in effects that it tumor cell immune response by and W. G. J. B. G. in T-cell and PubMed Scopus Google Scholar, M. Chang Chang M. Cheng M. T cell on of glutamine and Full Text Full Text PDF PubMed Scopus Google Scholar). In addition, immune as expression on tumor cells via or G. Chen L. D. D. H. expression via of in Cancer Res. PubMed Scopus Google Scholar, M. S. J. of glutamine with immune checkpoint inhibitor to antitumor Full Text Full Text PDF PubMed Scopus Google Scholar). of glutamine a antitumor strategy. V9302 is a and small-molecule of that V9302 a antitumor the other and M. A. P. J. L. S. J. R. M. J. J. M. J. J. M. et of glutamine to antitumor in 2018; 24: PubMed Scopus Google Scholar). 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W. autophagy to and 2019; 24: Full Text Full Text PDF PubMed Scopus Google Scholar). was reported to by L. S. S. of and in and breast J. 2021; PubMed Scopus Google Scholar). autophagy was to we which the cell to We that cell and and production In addition, with B7H3 and cells and CD8+ we cell from by to to and V9302 with or we cells with by cell and that and expression on CD8+ and Collectively, that the cell and death by V9302, antitumor immunity by V9302 via Despite the enormous successes of anti-PD-1/PD-L1 immunotherapy in multiple the overall response rates of breast cancer remain suboptimal. of B7H3 was reported to therapeutic effects and anti-PD-1 therapy in multiple mouse tumor models. V9302 breast cancer to antibody, we and breast tumor cells to syngeneic models. was reported that tumors A. E. from breast Res. Google Scholar, R. L.A. S. of endocrine breast cancer: and 2021; Google Scholar, A. A. is it a cell for mouse cancer and PubMed Scopus Google and tumors F. M. J. 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S. et and of in a phase breast cancer in breast cancer the of to with Clin. Oncol. PubMed Scopus Google Scholar, S. S. L. S. M. et of in triple-negative breast cancers from phase breast cancer and Clin. Oncol. PubMed Scopus Google Scholar, S. S. Salgado R. V. D. P.L. P. V. C. S. C. H. et in breast cancer and for in breast cancer: from the Oncol. Full Text Full Text PDF PubMed Scopus Google Scholar, C. von G. S. R. C. Loi S. C. K. S. K. C. et and response to chemotherapy with or in epidermal growth factor receptor and triple-negative breast Clin. Oncol. PubMed Scopus Google Scholar). We the of V9302 and anti-PD-1 was related to CD8+ by and and of B7H3 the immune The showed that anti-PD-1 antibody a effect on CD8+ while V9302 CD8+ T cells in tumor tissues. 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R. et to tumor immune 2019; PubMed Scopus Google Scholar). that of cancer cells with the of and in tumor tissue tumor growth and the of an antitumor immune Therefore, to that enhances In our we of with a small-molecule inhibitor V9302 tumor cell and cell In of the of V9302 in the effects in the V9302 a antitumor immune response as it and in tumor and the of anti-PD-1 mAb to block tumor or of monotherapy to a tumor which on the and of CD8+ T cells a immune as the tumors L. J. A. R.L. E. J. R. et to tumor immune 2019; PubMed Scopus Google Scholar). cells in of in the and of and and tumor of to CD8+ T cells L. W. R.L. J. L. et glutamine enhances immunity by Clin. PubMed Scopus Google Scholar). which is strategy to block of or of inhibitor T and in both a mouse and S. S. Chen J. glutamine in tumor cells antitumor T activity in triple-negative breast Clin. 2021; Scopus Google Scholar). inhibitor treatment of and a antitumor immune response H. S. G. Cheng M. C. K. M. 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M. et of glutamine to antitumor in 2018; 24: PubMed Scopus Google Scholar). Furthermore, inhibitors cells to and immune cells and of the antitumor immune the effects by immune checkpoint with the expression of and B7H3 in cancer and decreases expression in the CD8+ T in a improved to anti-PD-1 immune therapy Gupta R. K. B. A. V. A. S. cancer to Clin. PubMed Scopus Google Scholar). of in expression both in tumor cells and cells. with combined with anti-PD-1 or tumor was monotherapy L. W. R.L. J. L. et glutamine enhances immunity by Clin. PubMed Scopus Google Scholar). In the treatment with and anti-PD-1 and of expression in CD8+ T cells or and T cells leading to improved antitumor effects compared with anti-PD-1 monotherapy L. J. A. R.L. E. J. R. et to tumor immune 2019; PubMed Scopus Google Scholar). and inhibitors reported to with immune checkpoint by In our we that V9302 anti-PD-1 in the “immune breast cancer and K. R.L. L.A. B. S. of metastatic mouse cancers to immune checkpoint by of S. A. PubMed Scopus Google syngeneic cancer with CD8+ T-cell and and most breast cancers among which is the most with and Though patients with from the of anti-PD-1/PD-L1 antibody with chemotherapy P. H.S. S. A. H. V. V. L. V. A. Loi S. Emens L.A. et as treatment for locally advanced or metastatic triple-negative breast cancer from a phase Oncol. Full Text Full Text PDF PubMed Scopus Google Scholar), a small of patients with breast Therefore, to immunotherapy and treatment strategy B7H3 is specifically overexpressed in breast cancer compared with normal breast tissue and benign L. Breast cancer by Res. PubMed Scopus Google Scholar). has been as a T-cell coinhibitory and to with of in H. and PD-1, and or 2019; PubMed Scopus Google Scholar). In including breast cell cancer and and therapy the tumor related to the of S. L. M. S. K. S. immune checkpoint and 2019; PubMed Scopus Google Scholar, P. J. P. H. M. Chang W. W. L. et of the immune checkpoint tumor growth by enhancing Res. PubMed Scopus Google Scholar, C. L. J. P. W. expression cell cells to immune 2021; Full Text Full Text PDF PubMed Scopus Google Scholar). Therefore, B7H3 may an attractive for cancer immunotherapy. In the mechanism of immunotherapy we for the that V9302 the expression of B7H3, which to T-cell activity in breast cancers to therapy. with the in that CD8+ and combined with anti-PD-L1 antibody, the antitumor K. K. S. H. R. K. H. M. S. K. et negatively cancer Cancer Res. 2018; 24: PubMed Scopus Google Scholar, J. S. B. G. F. R. L. C. H. K. Chen G. et via receptor T cells and cell antitumor response of Oncol. 2021; PubMed Scopus Google Scholar). In which has a and is insensitive to anti-PD-1/PD-L1 therapy, B7H3 a in the of the expression of PD-L1, the of B7H3 in tumor cells T-cell D. J. D. S. P. S. L. L. L. C. the of antitumor T-cell in cancer insensitive to PubMed Scopus Google Scholar). B7H3 combined with anti-PD-1/PD-L1 as a potential therapeutic strategy to T cell and antitumor immunity in breast cancer patients to the of is that we that V9302 B7H3 expression by and in that the of in the that autophagy following V9302 was in multiple cell which was the and and autophagy PubMed Scopus Google Scholar). V9302 the activity of B7H3 we by using inhibitors The inhibitor B7H3 expression in the of V9302, while the of of V9302, the of In autophagy inhibitor A1 B7H3 Furthermore, block of by the expression of B7H3 in the of V9302 the to B7H3 expression and the following immune that the and autophagic of the of the by autophagy to the levels of The of of which the autophagy and autophagic of by or and that of or the autophagy with the in response to V9302 and the effects of on and B7H3 to R. of autophagy by and Full Text Full Text PDF PubMed Scopus Google Scholar, J. J. of autophagy by From to 2021; Scopus Google Scholar, and PubMed Scopus Google Scholar). In we reported a mechanism of glutamine antitumor immune response in breast that of the expression of T-cell coinhibitory B7H3 by autophagy the immunotherapy strategy of anti-PD-1 with to CD8+ T-cell and antitumor immune response B7H3 mAb anti-PD-1 mAb has been in phase clinical in patients with cell of the and and cancer and showed antitumor effects and K. M. in cancer immune 2018; Full Text Full Text PDF PubMed Scopus Google Scholar). has in anti-PD-1/PD-L1 mAb with B7H3 mAb or immunotherapy for or breast cancer to and patients with metastatic or advanced breast is a of and clinical trials to and the of immunotherapy in breast from patients with breast the 2020 and and for B7H3, and and in and for CD8+ and tumor from patients and related with the of the and of the and with B7H3 and or mouse B7H3 and by and with antibody or with and for the of cell was following the of the The of B7H3 was as the of the of cells and as B. L. C. L. H. F. D. M. E. A and breast cancer Full Text Full Text PDF PubMed Scopus Google Scholar), and to 10 tumor for The antibody was to the which as of tissue by the number of autophagic in cell to autophagic CD8+ was as the of to tumor following of the tumor L.A. L. Loi S. H.S. A. V. H. M. A. A. S. P. and in advanced triple-negative breast cancer: of the study.J. Cancer 2021; PubMed Scopus Google Scholar). and breast cancer cell lines from the and to the with bafilomycin A1 for to B7H3 and of V9302 was to tumor cells for in the in the or of for and tumor or with or to B7H3 and in or and with V9302 for cell was using to the and cell was by and by was using as a and by in with the cells by with a inhibitor was using the of the by and to with the with B7H3 or antibody and antibody as and by tumor with small in and with for a and and cell and with and and or and B7H3 for The in and cells from by as S. Chen J. Chen J. Chen F. C. D. W. L. W. J. F. H. H. et cancer cells and is to breast cancer Full Text Full Text PDF PubMed Scopus Google Scholar). by in with for in a with and for to tumor cell been as a of for D. Chen J. L. J. L. J. J. Chen F. F. H. S. et tumor immune by T cells to cell 2018; PubMed Scopus Google Scholar). tumor cells or with as in lines and in 1 and by The for to cell and the to for CD8+ T cells by CD8+ T and in with cells with tumor in for to granzyme B and by and using and by the and of syngeneic and breast cancer cells the of to and tumors a of to of the following by a anti-PD-1 antibody 10 a V9302 or V9302 growth was by tumor and was using the the in the for and A was for analysis was to the B7H3 and for and with compared by of the the was to the effects of of was to the analysis was using was for a of was to the as in the was and by the and of the with The treatment of in to the and of The was from other in the and The is of with the of We for with We the patients to in the was by from and and and of and of D. and H. L. J. and W. L. and H. L. F. and H. W. and L. C. W. D. W. and S. L. L. and L. H. L. and with with

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