Role of Tissue-Resident Memory in Intra-Tumor Heterogeneity and Response to Immune Checkpoint Blockade

Abstract

Tissue-resident memory T (T_RM) cells are a distinct subset of memory T cells that reside in non-lymphoid tissues for prolonged periods of time without significant recirculation providing continued immune surveillance at these sites. Recent studies suggest that T_RM cells are also enriched within tumor tissue. Expression of inhibitory immune checkpoints (ICPs) is particularly enriched on this subset of tumor-infiltrating T cells, suggesting that they are major targets for newer therapies targeting ICPs such as the programmed death-1 pathway. Recent studies suggest that tissue restriction of these cells without recirculation may also lead to heterogeneity of T_RM cells within individual metastatic lesions, ultimately leading to inter-lesional diversity. Thus, individual metastatic lesions may contain genomically distinct immune microenvironments that impact both evolution of tumors as well as the mechanisms underlying response and resistance to immune therapies. Understanding the biology of T_RM cells infiltrating tumors will be essential to improving immune-based approaches in diverse settings.

Keywords: cancer immunotherapy; immune checkpoint blockade; immunity to cancer; tissue-resident memory cells; tumor heterogeneity.

Figure 1

Inter-lesional heterogeneity in metastatic cancer and biology of tissue-resident memory (T_RM) cells. T_RM T cells were identified in mice based on their restriction to non-lymphoid tissues and lack of recirculation. This was demonstrated using parabiotic mice (A) that share the same systemic circulation. Figure shows that T_RM cells in the skin (blue/green) do not equilibrate between mice, while other effector/memory T cells (pink/red) do. In the setting of advanced cancer in humans (B), individual metastatic lesions can be observed in diverse tissues that share systemic circulation analogous to the parabiotic mice. Sequencing of T cell receptors (TCRs) in individual lesions from the same patient demonstrated that dominant TCRs in each of the lesions were non-overlapping and that the inter-lesional heterogeneity of TCRs exceeded differences in neoantigens. Importantly, T_RM cells were the major contributors to this heterogeneity suggesting that they do not equilibrate between lesions as in parabiotic mice in Ref. (25). A subset of T_RM cells that infiltrate these tumors express inhibitory immune checkpoints such as PD1 (shown by bolded outlines).