T-cell and NK-cell infiltration into solid tumors: a key limiting factor for efficacious cancer immunotherapy

Abstract

Cancer immunotherapy has great promise, but is limited by diverse mechanisms used by tumors to prevent sustained antitumor immune responses. Tumors disrupt antigen presentation, T/NK-cell activation, and T/NK-cell homing through soluble and cell-surface mediators, the vasculature, and immunosuppressive cells such as myeloid-derived suppressor cells and regulatory T cells. However, many molecular mechanisms preventing the efficacy of antitumor immunity have been identified and can be disrupted by combination immunotherapy. Here, we examine immunosuppressive mechanisms exploited by tumors and provide insights into the therapies under development to overcome them, focusing on lymphocyte traffic.

Figure 1

Schematic representation of tumor microenvironment with leukocytes entering through blood capillaries and exiting via afferent lymphatic vessels. Antitumor mechanisms favoring the entrance of tumor-destroying leukocytes are depicted in green. Protumor mechanisms based on the interference with effector and memory T-cell entrance, entrance of Tregs, and MDSCs are represented in red. Efferent lymphatic (V) vessels control traffic of DCs ferrying antigen cargo to draining lymph nodes and may play a vital role in recirculation of memory T lymphocytes. dsRNA, double-stranded RNA; LPS, lipopolysaccharide; APC, antigen-presenting cells; PAMP, pathogen associated molecular pattern; IDO, indoleamine 2,3-dioxygenase; DC, dendritic cell; MDSC, myeloid-derived suppressor cell.