Immune correlates of melanoma survival in adoptive cell therapy

Abstract

The advent of immunotherapies for cancer has resulted in robust clinical responses and confirmed that the immune system can significantly inhibit tumor progression. The recent success of adoptive cell therapy against melanoma suggests that endogenous T-cell responses have the potential to control cancer. However, the lack of responses in some patients receiving such therapy indicates a need for a better understanding of the host immune response to solid tumors. In this review, we summarize the current knowledge on the characteristics of adoptively transferred T cells associated with successful anti-melanoma immune responses in humans.

Keywords: CD8+ cells; TILs; adoptive cell therapy; memory T cells.

Figure 1. Cell surface phenotypes in melanoma. On the left (green): cell surface markers associated with melanoma survival. Co-stimulatory molecules: CD27 and CD28; activation markers: CD107a, CD69, CD134 (OX40) and CD25 (IL-2Rα); cytokine receptors that promote T-cell survival: CD25 (IL-2Rα) and IL-7R; memory T-cell markers: CD45RO, CD62L, and CCR7. On right (pink): cell surface markers associated with melanoma progression. Inhibitory receptors, CTLA-4 and PD-1.

Figure 2. Functional T-cell populations in tumor immunity. Antitumor T-cell functions. Cytotoxic CD8⁺ T lymphocytes (CTLs) directly kill tumor cells by releasing cytotoxic granules containing perforin and granzymes and secrete interleukin (IL)-2, interferon (IFN)γ, and tumor necrosis factor (TNF)α, which contribute to antitumor functions in several ways. IL-2 promotes CD8⁺ cell survival and proliferation. IFNγ enhances CD4⁺ T_H1 cell differentiation, inhibits angiogenesis, and activates antitumor biochemical pathways in macrophages and dendritic cells (DCs) (not shown). TNFα directly induces tumor cell death and promotes CD8⁺ cell proliferation and recruitment. CD4⁺ T_H1 cells promote antitumor responses by secreting IL-2 and IFNγ and prime DCs to activate CD8⁺ T cells through CD40-CD40 ligand (CD40L) interactions. T_H17 cells secrete IFNγ and IL-17, the latter of which induces tumor cells to release CCL2 and CCL20, which promote DC recruitment to tumor tissues. DCs bearing tumor antigens migrate to draining lymph nodes and activate tumor-specific CD8⁺ T cells. In mice, T_H9 cells directly kill tumor cells through the release of granzymes and secrete IL-9, which promotes antitumor responses through an unknown mechanism that involves mast cells. T_H22 cells secrete IL-22 and TNFα, which activates keratinocytes to produce antimicrobial peptides that exhibit antitumor activity. Pro-tumor T-cell functions. T_H2 cells facilitate tumor growth by inhibiting the functions of T_H1 cells. Naturally occurring regulatory T cells expressing CD25 and FOXP3 also promote tumor cell growth by suppressing the proliferation and activation of effector T cells.