The Paradox of Cancer Immune Exclusion: Immune Oncology Next Frontier.

Checkpoint inhibitor therapy (CIT) has revolutionized cancer treatment but it has also reached a standstill when an absent dialog between cancer and immune cells makes it irrelevant. This occurs with high prevalence in the context of "immune silent" and, even perhaps, "immune-excluded" tumors. The latter are characterized by T cells restricted to the periphery of cancer nests. Since in either case T cells do not come in direct contact with most cancer cells, CIT rests immaterial. Adoptive cell therapy (ACT), may also be affected by limited access to antigen-bearing cancer cells. While lack of immunogenicity intuitively explains the immune silent phenotype, immune exclusion is perplexing. The presence of T cells at the periphery suggests that chemo-attraction recruits them and an immunogenic stimulus promotes their persistence. However, what stops the T cells from infiltrating the tumors' nests and reaching the germinal center (GC)? Possibly, a concentric gradient of increased chemo-repulsion or decreased chemo-attraction demarcates an abrupt "do not trespass" warning. Various hypotheses suggest physical or functional barriers but no definitive consensus exists over the weight that each plays in human cancers. On one hand, it could be hypothesized that the intrinsic biology of cancer cells may degenerate from a "cancer stem cell" (CSC)-like phenotype in the GC toward a progressively more immunogenic phenotype prone to immunogenic cell death (ICD) at the periphery. On the other hand, the intrinsic biology of the cancer cells may not change but it is the disorderly architecture of the tumor microenvironment (TME) that alters in a centripetal direction cancer cell metabolism, both directly and indirectly, the function of surrounding stromal cells. In this chapter, we examine whether the paradoxical exclusion of T cells from tumors may serve as a model to understand the requirements for tumor immune infiltration and, correspondingly, we put forth strategies to restore the dialog between immune cells and cancer to enhance the effectiveness of immune oncology (IO) approaches.