Citations

Immune checkpoint therapy with PD-1 blockade has emerged as an effective therapy for many advanced cancers; however, only a small fraction of patients achieve durable responses. To date, there is no validated blood-based means of predicting the response to PD-1 blockade. We report that Bim is a downstream signaling molecule of the PD-1 pathway, and its detection in T cells is significantly associated with expression of PD-1 and effector T cell markers. High levels of Bim in circulating tumor-reactive (PD-1 + CD11a hi CD8 + ) T cells were prognostic of poor survival in patients with metastatic melanoma who did not receive anti–PD-1 therapy and were also predictive of clinical benefit in patients with metastatic melanoma who were treated with anti–PD-1 therapy. Moreover, this circulating tumor-reactive T cell population significantly decreased after successful anti–PD-1 therapy. Our study supports a crucial role of Bim in both T cell activation and apoptosis as regulated by PD-1 and PD-L1 interactions in effector CD8 + T cells. Measurement of Bim levels in circulating T cells of patients with cancer may provide a less invasive strategy to predict and monitor responses to anti–PD-1 therapy, although future prospective analyses are needed to validate its utility.

The use of programmed cell death 1 ligand 1 (PD‐L1) as a predictive biomarker to select patients to receive programmed cell death 1 (PD‐1) or PD‐L1 inhibitors in non‐small cell lung cancer (NSCLC) is limited by the definitions of positivity, interassay agreement, and intra‐ and intertumoral heterogeneity of expression. Although PD‐L1 expression enriches for responses, the lack of expression does not exclude clinical benefit.

Abstract The PD-1:PD-L1 immune signaling axis mediates suppression of T-cell–dependent tumor immunity. PD-1 expression was recently found to be upregulated on tumor-infiltrating murine (CD11c+CD11b+CD8−CD209a+) and human (CD1c+CD19−) myeloid dendritic cells (TIDC), an innate immune cell type also implicated in immune escape. However, there is little knowledge concerning how PD-1 regulates innate immune cells. In this study, we examined the role of PD-1 in TIDCs derived from mice bearing ovarian tumors. Similar to lymphocytes, TIDC expression of PD-1 was associated with expression of the adapter protein SHP-2, which signals to NF-κB; however, in contrast to its role in lymphocytes, we found that expression of PD-1 in TIDC tonically paralyzed NF-κB activation. Further mechanistic investigations showed that PD-1 blocked NF-κB–dependent cytokine release in a SHP-2–dependent manner. Conversely, inhibition of NF-κB–mediated antigen presentation by PD-1 occurred independently of SHP-2. Collectively, our findings revealed that PD-1 acts in a distinct manner in innate immune cells compared with adaptive immune cells, prompting further investigations of the signaling pathways controlled by this central mediator of immune escape in cancer. Cancer Res; 76(2); 239–50. ©2015 AACR.

Abstract Targeting membrane PD-1 molecules expressed by tumor-reactive T cells is gaining acceptance as a potentially effective anti-tumor immunotherapy. PD-1 blockade mediated by monoclonal antibodies has yielded promising therapeutic effects in treatment of melanoma, lung cancer and kidney cancers. Although detecting PD-1 expression by T cells is relatively straightforward, a simple and reliable method for determining whether PD-1 on T cells has engaged its ligand B7-H1 (PD-L1) is wanting. Our previous studies have revealed that engagement of PD-1 or B7-1 by B7-H1 results in alternations of apoptosis signaling pathway by up-regulating pro-apoptotic molecules among activated T cells and are correlated with B7-H1-mediated T cell death. Those observations suggest that intracellular levels of apoptosis-related Bcl2 family molecules among PD-1 positive CD8 T cells may be barometers of the extent to which PD-1 has been triggered by B7-H1. Using PD-1 and B7-H1 deficient animal models, we found that lower levels of intracellular pro-apoptosis molecules identify those activated T cells whose PD-1 molecules have not yet been extensively engaged, thus T cell function might be restored to their normal function once PD-1 signals from B7-H1 are blocked. Similarly, human PD-1 positive CD8 T cells engaged by B7-H1 also expressed higher levels of pro-apoptosis molecules during antigen stimulation. Our clinical data demonstrated that pro-apoptosis molecule expression by tumor-reactive T cell levels are higher among advanced melanoma and prostate cancers than healthy controls, reflecting chronic engagement with B7-H1. Thus, using pro-apoptosis status as signaling biomarkers for T cell PD-1 engagement, it may be possible to select patients who are most likely to have strong benefit from PD-1 or B7-H1 (PD-L1) blockade therapy. Citation Format: Wei Zhao, Haidong Dong. T cell apoptosis signaling biomarker of PD-1 engagement in cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2552. doi:10.1158/1538-7445.AM2014-2552

Abstract Development of resistance to chemotherapy and immunotherapy is a major obstacle in extending the survival of cancer patients. Although several molecular mechanisms have been identified that can contribute to chemoresistance, the role of immune checkpoint molecules in tumor chemoresistance has received little consideration. Elevated expression of B7-H1 (also named PD-L1) is predictive of an aggressive disease course, including increases in disease progression and cancer-related mortality in a variety of cancers (ovary, breast, liver, pancreas, esophagus, colon and lung). Although the aggressiveness of B7-H1 positive tumors has been attributed to B7-H1's immune-suppressive function, B7-H1 itself may be directly altering tumor cell intracellular signaling pathways promoting acquisition of drug resistance. It has been reported that overexpression of B7-H1 confers chemoresistance in human cancers. However, the mechanisms by which B7-H1 contributes to tumor chemoresistance have yet to be defined. We show that B7-H1 transfected tumor cells are resistant to chemotherapy. This resistance is due to increased activation of MAPK/ERK pathway in tumor cells with B7-H1 overexpression. Inhibition of ERK activation restored drug sensitivity of B7-H1 positive tumor cells. We further analyzed the downstream elements of B7-H1 signaling pathway and identified a new B7-H1 associated protein that is involved in DNA damage repair and MAPK/ERK activation mechanisms. We conclude that B7-H1 mediates tumor chemoresistance by enhancing the activation of MAPK/ERK pathway via its intracellular signaling pathway. Our studies may identify a novel pharmaceutical target for treatment of B7-H1 positive refractory tumor cells. Citation Format: Amanda Orzechowski, Haidong Dong. B7-H1 confers tumor chemoresistance by regulating MAPK/ERK activation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5026. doi:10.1158/1538-7445.AM2014-5026

Abstract We investigated the influence of PD-1 expression on the systemic antitumor response (abscopal effect) induced by stereotactic ablative radiotherapy (SABR) in preclinical melanoma and renal cell carcinoma models. We compared the SABR-induced antitumor response in PD-1–expressing wild-type (WT) and PD-1–deficient knockout (KO) mice and found that PD-1 expression compromises the survival of tumor-bearing mice treated with SABR. None of the PD-1 WT mice survived beyond 25 days, whereas 20% of the PD-1 KO mice survived beyond 40 days. Similarly, PD-1–blocking antibody in WT mice was able to recapitulate SABR-induced antitumor responses observed in PD-1 KO mice and led to increased survival. The combination of SABR plus PD-1 blockade induced near complete regression of the irradiated primary tumor (synergistic effect), as opposed to SABR alone or SABR plus control antibody. The combination of SABR plus PD-1 blockade therapy elicited a 66% reduction in size of nonirradiated, secondary tumors outside the SABR radiation field (abscopal effect). The observed abscopal effect was tumor specific and was not dependent on tumor histology or host genetic background. The CD11ahigh CD8+ T-cell phenotype identifies a tumor-reactive population, which was associated in frequency and function with a SABR-induced antitumor immune response in PD-1 KO mice. We conclude that SABR induces an abscopal tumor-specific immune response in both the irradiated and nonirradiated tumors, which is potentiated by PD-1 blockade. The combination of SABR and PD-1 blockade has the potential to translate into a potent immunotherapy strategy in the management of patients with metastatic cancer. Cancer Immunol Res; 3(6); 610–9. ©2015 AACR.

Abstract Immune checkpoint blockade therapies have demonstrated promising therapeutic effects; however, clinical outcomes are variable, with only a subgroup of cancer patients achieving durable complete responses. New therapeutic strategies, including local administration of immunomodulatory antibodies, have been considered as better routes for improving the overall efficacy of antibody-based therapy. Clin Cancer Res; 21(5); 944–6. ©2014 AACR. See related articles by Mangsbo et al., p. 1115, and Dai et al., p. 1127