Abstract SY41-04: Immune suppression by T cell exclusion in pancreatic cancer

Abstract

In 1960, Klein and colleagues found that when mice developed primary methylcholanthrene-induced sarcomas, they also developed an acquired immune resistance mediated by lymph node cells to a secondary challenge comprised of cancer cells derived from the primary tumor. The paradoxical and critical finding of the study was that this anti-cancer immune response did not control the growth of the primary tumor, despite its ability to prevent the establishment of a secondary tumor comprised of cancer cells derived from the primary tumor. The primary tumor evaded immune control by establishing an immune suppressive tumor microenvironment (TME).

Unambiguous evidence for the inability in humans of a systemic immune response to eliminate immunogenic cancer cells was provided by Boon's studies thirty years later of the antigens that elicit specific CD8+ T cell responses in melanoma patients. Cloned CD8+ T cells from a melanoma patient were used to identify the antigen expressed by that patient's cancer: MAGE-A1. The explicit demonstration of the co-existence of a progressing melanoma with melanoma-specific T cells in this patient implicitly raised the question of why the T cells did not control the growth of the cancer. Moreover, Rosenberg and colleagues reported evidence of disease recurrence in melanoma patients despite very high levels of vaccine-induced circulating T cells and no evidence of antigen loss.

The discovery of melanoma-specific T cells in patients led not only to vaccine strategies to increase the frequency of cancer-specific T cells in patients, but also to a more direct means for accomplishing this goal, that of adoptively transferring large numbers of in vitro expanded tumor-infiltrating lymphocytes. This approach has shown some efficacy, but has not had the dramatic success of adoptively transferring virus-specific CD8+ T cells to immunodeficient bone marrow transplant recipients with CMV infection or EBV-associated lymphoproliferative disorders. Differences in the microenvironments of virally infected tissues and cancers must account for these distinct outcomes.

The more recent strategy of enhancing the function of effector T cells by targeting CTLA-4 and PD-1, immunoregulatory receptors on T cells, has been successful in subsets of patients with melanoma, NSCLC, bladder cancer, and renal cell cancer. Nevertheless, it has become apparent that even if these T cell checkpoint antagonists overcome some of the immune suppressive effects of the TME, there must be other, more fundamental inhibitory reactions in the TME to explain why most patients, especially those with colorectal cancer (CRC), ovarian cancer, prostate cancer, and pancreatic ductal adenocarcinoma (PDAC) do not exhibit objective responses to these therapies.

A clue to the nature of this dominant immune suppression mediated by the TME comes from studies that have examined the spatial relationship of CD8+ effector T cells to cancer cells in three of the tumors that do not respond to anti-PD-1/anti-PD-L1: CRC, ovarian cancer and PDA. In each of these cancers, CD8+ T cells are excluded from cancer cell nests, and correlates with a poor long term clinical outcome. Thus, the TME can limit the capacity of T cells to accumulate amongst cancer cells, and one must conclude that until this problem is overcome, the full potential of other approaches to T cell-mediated tumor immunotherapy will not be realized.

Recent studies have begun to explain how this form of immune suppression is mediated. Pre-clinical studies in mouse models of cancer now implicate the major stromal cell types of the TME, cancer-associated fibroblasts (CAFs) and myelomonocytic cells as being responsible for restricting the accumulation of T cells in the vicinity of cancer cells. As would be predicted, overcoming this restriction has revealed the anti-tumor effects of T cell checkpoint antagonists that had been ineffective when administered as monotherapy.

I will discuss my group's recent studies of how the CAF mediates the exclusion of T cells in an autochthonous moue model of PDAC. The discovery the mechanism of exclusion has led to a potential therapeutic approach that revealed the existence of a previously unsuspected spontaneous anti-cancer immune response in these mice, and uncovered the efficacy of the anti-PD-L1 T cell checkpoint antagonist.

Citation Format: Douglas T. Fearon. Immune suppression by T cell exclusion in pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY41-04. doi:10.1158/1538-7445.AM2015-SY41-04