The effect of organ-specific tumor microenvironments on response patterns to immunotherapy

Abstract

Immunotherapy, particularly immune checkpoint inhibitors, have become widely used in various settings across many different cancer types in recent years. Whilst patients are often treated on the basis of the primary cancer type and clinical stage, recent studies have highlighted disparity in response to immune checkpoint inhibitors at different sites of metastasis, and their impact on overall response and survival. Studies exploring the tumor immune microenvironment at different organ sites have provided insights into the immune-related mechanisms behind organ-specific patterns of response to immunotherapy. In this review, we aimed to highlight the key learnings from clinical studies across various cancers including melanoma, lung cancer, renal cell carcinoma, colorectal cancer, breast cancer and others, assessing the association of site of metastasis and response to immune checkpoint inhibitors. We also summarize the key clinical and pre-clinical findings from studies exploring the immune microenvironment of specific sites of metastasis. Ultimately, further characterization of the tumor immune microenvironment at different metastatic sites, and understanding the biological drivers of these differences, may identify organ-specific mechanisms of resistance, which will lead to more personalized treatment approaches for patients with innate or acquired resistance to immunotherapy.

Keywords: immunotherapy; metastasis; organ-specific immune microenvironment; organ-specific immune response; tumor microenvironment.

Figure 1

The immune microenvironment in lung, brain, liver and bone metastases. (A) Lung metastasis showing a higher infiltration of T cells, macrophages, dendritic cells, B cells, fibroblasts and CD11b+ NK cells compared with other sites of metastases (e.g. liver, brain, and bone). There is increased T cell expression of PD-1 and increased tumor and macrophage expression of PD-L1 compared with other sites of metastases (e.g. liver, and brain). B) Brain metastasis showing a higher infiltration of M2 macrophages and reduced infiltration of T cells compared with other metastases (e.g. lung). There is also increased T cell expression of PD-1 compared with other metastases (e.g. liver) and a disrupted blood brain barrier. (C) Liver metastasis showing reduced infiltration of T cells but increased infiltration of macrophages including M2 macrophages, and CD27+ NK cells compared with other metastases (e.g. lung and bone) There is also reduced T cell expression of PD-1 and high T cell expression of Tim-3 compared with other metastases (e.g. brain, lung, and bone). Increased T cell apoptosis has been observed. (D) Bone metastasis showing an increased infiltration of fibroblasts and stromal cells compared with other metastases (e.g. liver and brain). There is also increased tumor expression of PD-L1 and VCAM-1 compared with other metastases (e.g. liver and brain). An increase in the RANKL pathway leading to increased osteoclasts and subsequently increased osteoclast driven bone resorption is also observed in bone metastases. ↑ = Increased cell infiltration ↓ = Decreased cell infiltration ⇧ = Increased expression ⇩ = Decreased expression TME = Tumor microenvironment. Created with BioRender.com.