Anti-PD-1 increases the clonality and activity of tumor infiltrating antigen specific T cells induced by a potent immune therapy consisting of vaccine and metronomic cyclophosphamide (original) (raw)
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Cancer Immunology Immunotherapy, 2020
The expression of PD-L1 on tumor cells or within the tumor microenvironment has been associated with good prognosis and sustained clinical responses in immunotherapeutic regimens based on PD-L1/PD-1/CD80 immune checkpoint blockade. To look into the current controversy in cancer immunotherapy of the relative importance of PD-L1 expression on tumor cells versus non-tumor cells of the tumor microenvironment, a hematological mouse tumor model was chosen. By combining a genetic CRISPR/Cas9 and immunotherapeutic approach and using a syngeneic hematopoietic transplantable tumor model (E.G7-cOVA tumor cells), we demonstrated that dual blockade of PD-L1 interaction with PD-1 and CD80 enhanced anti-tumor immune responses that either delayed tumor growth or led to its complete eradication. PD-L1 expression on non-tumor cells of the tumor microenvironment was required for the promotion of tumor immune escape and its blockade elicited potent anti-tumor responses to PD-L1 WT and to PD-L1-deficient tumor cells. PD-L1 + tumors implanted in PD-L1-deficient mice exhibited delayed tumor growth independently of PD-L1 blockade. These findings emphasize that PD-L1 expression on non-tumor cells plays a major role in this tumor model. These observations should turn our attention to the tumor microenvironment in hematological malignancies because of its unappreciated contribution to create a conditioned niche for the tumor to grow and evade the anti-tumor immune response.
Clinical Cancer Research, 2014
Purpose: Immunomodulatory drugs differ in mechanism-of-action from directly cytotoxic cancer therapies. Identifying factors predicting clinical response could guide patient selection and therapeutic optimization. Experimental Design: Patients (N ¼ 41) with melanoma, non-small cell lung carcinoma (NSCLC), renal cell carcinoma (RCC), colorectal carcinoma, or castration-resistant prostate cancer were treated on an early-phase trial of anti-PD-1 (nivolumab) at one institution and had evaluable pretreatment tumor specimens. Immunoarchitectural features, including PD-1, PD-L1, and PD-L2 expression, patterns of immune cell infiltration, and lymphocyte subpopulations, were assessed for interrelationships and potential correlations with clinical outcomes. Results: Membranous (cell surface) PD-L1 expression by tumor cells and immune infiltrates varied significantly by tumor type and was most abundant in melanoma, NSCLC, and RCC. In the overall cohort, PD-L1 expression was geographically associated with infiltrating immune cells (P < 0.001), although lymphocyte-rich regions were not always associated with PD-L1 expression. Expression of PD-L1 by tumor cells and immune infiltrates was significantly associated with expression of PD-1 on lymphocytes. PD-L2, the second ligand for PD-1, was associated with PD-L1 expression. Tumor cell PD-L1 expression correlated with objective response to anti-PD-1 therapy, when analyzing either the specimen obtained closest to therapy or the highest scoring sample among multiple biopsies from individual patients. These correlations were stronger than borderline associations of PD-1 expression or the presence of intratumoral immune cell infiltrates with response. Conclusions: Tumor PD-L1 expression reflects an immune-active microenvironment and, while associated other immunosuppressive molecules, including PD-1 and PD-L2, is the single factor most closely correlated with response to anti-PD-1 blockade. Clin Cancer Res; 20(19); 5064-74. Ó2014 AACR.
Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway
Trends in molecular medicine, 2015
The programmed death 1 (PD-1) receptor and its ligands programmed death ligand 1 (PD-L1) and PD-L2, members of the CD28 and B7 families, play critical roles in T cell coinhibition and exhaustion. Overexpression of PD-L1 and PD-1 on tumor cells and tumor-infiltrating lymphocytes, respectively, correlates with poor disease outcome in some human cancers. Monoclonal antibodies (mAbs) blockading the PD-1/PD-L1 pathway have been developed for cancer immunotherapy via enhancing T cell functions. Clinical trials with mAbs to PD-1 and PD-L1 have shown impressive response rates in patients, particularly for melanoma, non-small-cell lung cancer (NSCLC), renal cell carcinoma (RCC), and bladder cancer. Further studies are needed to dissect the mechanisms of variable response rate, to identify biomarkers for clinical response, to develop small-molecule inhibitors, and to combine these treatments with other therapies.
Acta Scientific Microbiology, 2021
Immune checkpoints are a group of inhibitory mechanisms that are encoded into the immune system. Mice treated with anti-PD L1 or PD-1-deficient animals showed increased tumorigenesis and invasiveness in syngeneic hosts when compared to parental tumor cells lacking PD-L. The classical type of programmed cell death is distinguished by its morphological hallmarks of apoptosis and its reliance on de novo RNA and protein production. The PD-1 gene was active in both stimulated 2B4.11 and IL-3-depleted LyD9 cells. The findings imply that the genetic landscape of lung malignancies influences anti-PD-1 therapeutic responsiveness. Immune resistance can be overcome by blocking the inhibitory receptor programmed death 1 (PD-1), which is produced by T cells. An antibody that precisely targets PD-1, was considered for anticancer efficacy and safety. There is a link between PD-L1 expression on tumor cells and objective response. In patients with advanced malignancies such as non-small cell lung cancer, melanoma, and renalcell cancer, antibody-mediated PD-L1 inhibition resulted in long-term tumor shrinkage and disease stability.
Clinical Cancer Research, 2009
The interaction between programmed cell death 1 (PD-1), expressed by activated effector or regulatory T cells, and B7-H1 (PD-L1) and B7-DC (PD-L2) results in the inhibition of T-cell function. The aim of this study was to determine B7-H1, B7-DC, and PD-1 expression in cervical carcinoma. Experimental Design: A tissue microarray of a well-defined group of 115 patients was stained with antibodies against B7-H1 and B7-DC. Three-color fluorescent immunohistochemistry was used to study the number and phenotype of tumor-infiltrating T cells expressing PD-1. Additional analyses consisted of in vitro T-cell suppression assays. Results: B7-H1 was expressed in 19%, and B7-DC was expressed by 29% of the 115 tumors. PD-1 was expressed by more than half of both the infiltrating CD8+ T cells and CD4+Foxp3+ T cells, irrespective of B7-H1 or B7-DC expression by tumors. The expression of B7-H1 did not show a direct impact on patient survival. However, subgroup analysis revealed that patients with a relative excess of infiltrating regulatory T cells displayed a better survival when the tumor was B7-H1 positive (P = 0.033). Additional studies showed that the presence of B7-H1 during the activation of CD4+Foxp3+ regulatory T cells impaired their suppressive function in a functional in vitro assay. Conclusions: B7-H1 is expressed on only a minority of cervical cancers and does not influence the survival of patients with cervical cancer. PD-1 is expressed by a vast number of infiltrating CD8 T cells, suggesting that blocking of PD-1 could have therapeutic potential in cervical cancer patients. (Clin Cancer Res 2009;15(20):6341-7) Cervical cancer is the second most common cancer in women worldwide (1). It develops as a result of an uncontrolled persistent infection with a high-risk type of human papilloma virus (HPV), in particular, types HPV16 and HPV18 (2). The occurrence of HPV-induced cancer is strongly associated with failure to mount a strong HPV-specific type 1 T-helper and cytotoxic Tlymphocyte response (3-5), the lack of CD8+ T cells migrating into the tumor cell nests, the induction of HPV16-specific regulatory T cells, and the influx of regulatory T cells into the tumor (6, 7). Moreover, the ratio between the tumor-infiltrating CD8+ T cells and coinfiltrating CD4+Foxp3+ regulatory T cells is an independent prognostic factor for overall survival (8), indicating the key role of these different types of T cells in cervical cancer. Activated T cells can express the programmed cell death 1 (PD-1) receptor, which can bind B7-H1 (PD-L1) and B7-DC (PD-L2). B7-H1 could be induced to express by a wide variety of immune cells and nonhematopoetic cell types, whereas B7-DC is expressed mainly on activated macrophages and dendritic cells (9). Upon simultaneous engagement of both, the T-cell receptor and PD-1-negative immunoregulatory signals are transferred to the T cells, resulting in a decreased effector response and T-cell tolerance (10). PD-1/B7-H1 interactions have been shown to inhibit a wide range of immune responses against pathogen, tumor, and self-antigens (11, 12). More recently, it has been reported that B7-H1 and B7-DC are exploited by tumors to evade immune responses. B7-H1 is found to express on cell surface in most human cancers, and this expression was correlated with poor clinical prognosis in renal, gastric, ovarian, breast, and esophageal carcinomas (13-17). The role of B7-DC in the suppression of immune responses remains controversial (18). Because of the strong association between tumor-infiltrating lymphocytes (TIL) and the prognosis of cervical cancer (6, 8) and the fact that PD-1 has been reported to be expressed by tumor-infiltrating CD8+
Cancer Research, 2013
Head and neck cancers positive for human papillomavirus (HPV) have a more favorable clinical outcome than HPV-negative cancers, but it is unknown why this is the case. We hypothesized that prognosis was affected by intrinsic features of HPV-infected tumor cells or differences in host immune response. In this study, we focused on a comparison of regulatory Foxp3 þ T cells and programmed death-1 (PD-1) þ T cells in the microenvironment of tumors that were positive or negative for HPV, in two groups that were matched for various clinical and biologic parameters. HPV-positive head and neck cancers were more heavily infiltrated by regulatory T cells and PD-1 þ T cells and the levels of PD-1 þ cells were positively correlated with a favorable clinical outcome. In explaining this paradoxical result, we showed that these PD-1 þ T cells expressed activation markers and were functional after blockade of the PD-1-PD-L1 axis in vitro. Approximately 50% of PD-1 þ tumor-infiltrating T cells lacked Tim-3 expression and may indeed represent activated T cells. In mice, administration of a cancer vaccine increased PD-1 on T cells with concomitant tumor regression. In this setting, PD-1 blockade synergized with vaccine in eliciting antitumor efficacy. Our findings prompt a need to revisit the significance of PD-1-infiltrating T cells in cancer, where we suggest that PD-1 detection may reflect a previous immune response against tumors that might be reactivated by PD-1/PD-L1 blockade. Cancer Res; 73(1); 128-38. Ó2012 AACR.
Early T Cell Signalling Is Reversibly Altered in PD-1+ T Lymphocytes Infiltrating Human Tumors
PLoS ONE, 2011
To improve cancer immunotherapy, a better understanding of the weak efficiency of tumor-infiltrating T lymphocytes (TIL) is necessary. We have analyzed the functional state of human TIL immediately after resection of three types of tumors (NSCLC, melanoma and RCC). Several signalling pathways (calcium, phosphorylation of ERK and Akt) and cytokine secretion are affected to different extents in TIL, and show a partial spontaneous recovery within a few hours in culture. The global result is an anergy that is quite distinct from clonal anergy induced in vitro, and closer to adaptive tolerance in mice. PD-1 (programmed death -1) is systematically expressed by TIL and may contribute to their anergy by its mere expression, and not only when it interacts with its ligands PD-L1 or PD-L2, which are not expressed by every tumor. Indeed, the TCR-induced calcium and ERK responses were reduced in peripheral blood T cells transfected with PD-1. Inhibition by sodium stibogluconate of the SHP-1 and SHP-2 phosphatases that associate with several inhibitory receptors including PD-1, relieves part of the anergy apparent in TIL or in PD-1-transfected T cells. This work highlights some of the molecular modifications contributing to functional defects of human TIL.
Tumour and host cell PD-L1 is required to mediate suppression of anti-tumour immunity in mice
Nature communications, 2017
Expression of PD-L1, the ligand for T-cell inhibitory receptor PD-1, is one key immunosuppressive mechanism by which cancer avoids eradication by the immune system. Therapeutic use of blocking antibodies to PD-L1 or its receptor PD-1 has produced unparalleled, durable clinical responses, with highest likelihood of response seen in patients whose tumour or immune cells express PD-L1 before therapy. The significance of PD-L1 expression in each cell type has emerged as a central and controversial unknown in the clinical development of immunotherapeutics. Using genetic deletion in preclinical mouse models, here we show that PD-L1 from disparate cellular sources, including tumour cells, myeloid or other immune cells can similarly modulate the degree of cytotoxic T-cell function and activity in the tumour microenvironment. PD-L1 expression in both the host and tumour compartment contribute to immune suppression in a non-redundant fashion, suggesting that both sources could be predictive o...
PD-1, PD-L1 mechanism and cancer treatment
2021
In response to a foreign organism or material, our bodies react with a variety of immunological agents. This response mechanism is called immunogenicity. While some of the proteins that regulate the immune response function to activate this response, some of them are responsible for inhibiting this response. The main "brake" proteins involved in this negative regulation are cytotoxic T-lymphocyte-associated protein-4, programmed cell death protein-1 (PD-1), T-cell immunoglobulin and mucin domain-containing protein-3, and lymphocyte-activation gene-3. The cell can differentiate endogenous and exogenous substances through these brakes and other signal pathways. In the presence of brake proteins, the tumor cells are not perceived as a threat by the immune system, so a corresponding response does not occur. To generate this response, drugs containing monoclonal antibodies are produced for use in cancer treatments. Monoclonal antibodies are designed to block braking processes while also eliciting an immunological response. In this review, the PD-1 and programmed cell death-ligand 1 pathway and cancer immunotherapy are mentioned.
Seven different anti-PD-1 and PD-L1 monoclonal antibodies are now widely used in the US to treat a variety of cancer types, but there have been no clinical trials comparing them directly. Furthermore, because many of these antibodies do not cross react between mouse and human proteins, no preclinical models exist in which to consider these types of questions. Thus, we produced humanized PD-1 and PD-L1 mice in which the extracellular domains of both mouse PD-1 and PD-L1 were replaced with the corresponding human sequences. Using this new model, we sought to compare the strength of the immune response generated by FDA-approved antibodies. To do this, we performed an in vivo T cell priming assay in which anti-PD-1/L1 therapies were given at the time of T cell priming against surrogate tumor antigen (OVA), followed by subsequent B16-OVA tumor challenge. We found that anti-PD-1/L1-treated mice exhibited significantly better tumor rejection than controls, although both the control and ant...