Special Conference on Tumor Immunology and Immunotherapy: A New Chapter

Abstract

The overall objective of the fifth American Association for Cancer Research Special Conference on “Tumor Immunology and Immunotherapy: A New Chapter” organized by the Cancer Immunology Working Group was to highlight multidisciplinary approaches of immunotherapy and mechanisms related to the ability of immunotherapy to fight established tumors. With the FDA approval of sipuleucel-T, ipilimumab (anti-CTLA4; Bristol-Myers Squibb [BMS]), and the two anti-PD-1 antibodies, pembrolizumab (formerly MK-3475 or lambrolizumab; Merck) and nivolumab (BMS), immunotherapy has become a mainstream treatment option for some cancer. Many of the data presented at the conference and reviewed in this article showcase the progress made in determining the mechanistic reasons for the success of some treatments and the mechanisms associated with tolerance within the tumor microenvironment, both of which are potential targets for immunotherapy. In addition to combination and multimodal therapies, improvements in existing therapies will be needed to overcome the numerous ways that tumor-specific tolerance thwarts the immune system. This conference built upon the success of the 2012 conference, and focused on seven progressing and/or emerging areas that include: New combination therapies; Combination therapies and vaccine Improvement; Mechanisms of antibody therapy; Factors in the tumor microenvironment affecting the immune response; The microbiomes effect on cancer and immunotherapy; Metabolism in immunotherapy; and Adoptive T-cell therapy.

AKT-STAT3 Pathway as a Downstream Target of EGFR Signaling to Regulate PD-L1 Expression on NSCLC cells

“…Given the inhibition of both AKT and STAT3 did not show an additive effect on PD-L1 down-regulation, there should be the redundancy of AKT and STAT3 in the inhibition of PD-L1 expression on EGFR-activated cells. Considering recent attention of immunotherapy by modulating PD-1/PD-L1 interaction between the host immune system and cancer cells 5 , 9 , our present findings pave the way for sensitizing gefitinib-resistant NSCLCs to endogenous anti-tumor host immune response and/or T cell-dependent immunotherapy. Although it has been known that the inhibition of EGFR signaling can attenuate PD-L1 expression on NSCLCs 8 , 20 , 29 , there was no link between AKT-STAT3 pathways to regulate PD-L1 expression on NSCLCs as a downstream of EGFR signaling.…”

“…In the context of cancer, specific genomic subsets and oncogenic mutations are known to correlate to the expression level of PD-L1 on cancer cells, which is a specific ligand for PD-1, leading to T cells inactivation and subsequent escape from immune-surveillance 6 - 8 . Given the importance of the interaction between PD-1 and its ligands for cancer cells escaping from the host immune responses, an inhibition of PD-1/PD-L1 pathway has been shown to regain the effector function of antigen-specific T cells against cancer cells 5 , 9 .…”

Diacylglycerol Kinases (DGKs): Novel Targets for Improving T Cell Activity in Cancer

“…Given the enhanced functional activity conferred by loss of DGKs in T cells, our group and others have tested the hypothesis that these proteins may serve as useful targets for enhancing T cell anti-tumor activity. Recently, strategies to target negative regulators of T cells to enhance their anti-tumor activity have been successfully translated from basic science studies into clinical care (Byrne et al, 2015 ; Sharma and Allison, 2015 ; Shin and Ribas, 2015 ; Callahan et al, 2016 ). Although, antibodies directed against CTLA-4 and PD-1 are the most prominent examples of therapies that have generated clinical responses in human malignancy, there is significant interest in identifying additional inhibitory regulators of T cells to combine with existing approaches and to use in instances where blockade of PD-1 and other immune checkpoints is ineffective (Restifo et al, 2016 ).…”

Exploiting the neoantigen landscape for immunotherapy of pancreatic ductal adenocarcinoma

“…An alternative explanation for the resistance of PDAC to immunotherapy may be that while both neoantigens and corresponding TAA-reactive CD8 + TILs exist in PDAC, there is profound immune suppression that leads to ineffective T-cell activation and immune rejection. Such functional immune suppression, despite an effector T-cell influx, might be caused by the presence of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) and other inhibitory cytokines like TGFbeta and IL-10, all of which have been reported in the PDAC milieu 14 15 . In such cases, removal of immune suppression barriers, such as depletion of myeloid cells 16 , or artificially “boosting” the immune response through TAA-targeted vaccines or adoptively transferring T cells could enable overcoming tolerance 17 18 .…”