T-lymphocyte homing: an underappreciated yet critical hurdle for successful cancer immunotherapy

Abstract

Advances in cancer immunotherapy have offered new hope for patients with metastatic disease. This unfolding success story has been exemplified by a growing arsenal of novel immunotherapeutics, including blocking antibodies targeting immune checkpoint pathways, cancer vaccines, and adoptive cell therapy (ACT). Nonetheless, clinical benefit remains highly variable and patient-specific, in part, because all immunotherapeutic regimens vitally hinge on the capacity of endogenous and/or adoptively-transferred T effector (Teff) cells, including chimeric antigen receptor (CAR) T cells, to home efficiently into tumor target tissue. Thus, defects intrinsic to the multi-step T cell homing cascade have become an obvious, though significantly underappreciated contributor to immunotherapy resistance. Conspicuous have been low intralesional frequencies of tumor-infiltrating T-lymphocytes (TILs) below clinically beneficial threshold levels, and peripheral rather than deep lesional TIL infiltration. Therefore, a Teff cell ‘homing deficit’ may arguably represent a dominant factor responsible for ineffective immunotherapeutic outcomes, as tumors resistant to immune-targeted killing thrive in such permissive, immune-vacuous microenvironments. Fortunately, emerging data is shedding light into the diverse mechanisms of immune escape by which tumors restrict Teff cell trafficking and lesional penetrance. In this review, we scrutinize evolving knowledge on the molecular determinants of Teff cell navigation into tumors. By integrating recently described, though sporadic information of pivotal adhesive and chemokine homing signatures within the tumor microenvironment with better established paradigms of T cell trafficking under homeostatic or infectious disease scenarios, we seek to refine currently incomplete models of Teff cell entry into tumor tissue. We further summarize how cancers thwart homing to escape immune-mediated destruction and raise awareness of the potential impact of immune checkpoint blockers on Teff cell homing. Finally, we speculate on innovative therapeutic opportunities for augmenting Teff cell homing capabilities to improve immunotherapy-based tumor eradication in cancer patients, with special focus on malignant melanoma.

Chemokine receptor engineering of T cells with CXCR2 improves homing towards subcutaneous human melanomas in xenograft mouse model

“…While IL-8 may induce recruitment of T cells, T cells' extravasation and migration into peripheral tissues rely on selectin and integrin binding in concert with chemokine signaling to mediate rolling and firm adhesion to the endothelial wall. 17 , 36 Our xenograft model relies on stromal chemokines secreted by mouse endothelial cells and fibroblasts, and despite some sequence similarity and evolutionary conserved regions, there is a greater disparity, and these may not necessarily support T cell adhesion, extravasation and tumor infiltration. 37 In line with this, HEVs in human melanoma lesions have been shown to be major gateways for tumor infiltrating lymphocytes, 38 however lack of host immune cells in the NOG mouse model, and thus no orchestrating chemokines and cytokines, HEVs are most likely not produced in this model.…”

Tissue-Specific Immunoregulation: A Call for Better Understanding of the “Immunostat” in the Context of Cancer

“…The acquisition of highly specialized T-cell "homing" receptors, including adhesive receptors, chemokines, and other promigratory molecules, is critical to this process. Briefly, the steps in this cascade involve: (i) tethering and rolling adhesive interactions of the blood-borne cell onto the endothelial surface; (ii) integration of chemokine-mediated signaling within the milieu (via chemokine receptors expressed on the circulating cell), leading to integrin activation; (iii) integrin-mediated firm adherence of the cell onto the endothelial surface; and (iv) endothelial transmigration (46). Such trafficking and homing is organ-specific; indeed, the multistep homing mechanisms for T effector cell recruitment to skin and gut are already known to be distinct (46).…”

Research progress and design optimization of CAR‐T therapy for pancreatic ductal adenocarcinoma

“…T‐cell homing to solid tumors is regulated by strict molecular mechanisms. Significant obstacles preventing CTLs homing have been clearly revealed, including microvascular dysplasia, abnormal expression of adhesion molecule, chemokine‐chemokine receptor mismatching, immunoediting expression of TAA, and recruitment of CAF . Immunosuppressive microenvironment is another important factor that inhibit the function of T cells, which have been mentioned above.…”

“…PDAC cells can express chemokines (such as CCL2 and CCL5) and cytokines (such as GM-CSF, VEGF, and PDGF) to induce the chemotaxis of inflammatory cells into the tumor stroma, 4,5 but only a small proportion of them are cytotoxic T lymphocytes (CTL) because of the mismatch of chemokine receptors on CTLs, the abnormal development of interstitial vessels, and the downregulation of endothelial adhesion molecules. [6][7][8] In addition, cancer cells as well as Tregs, MDSCs, and M2 in the microenvironment can express Th2-type cytokines and immune checkpoints, which can not only aid these cells in maintaining their immunosuppressive phenotype, but can also inhibit the antitumor effect of CD4+T/CD8+T cells, 9 promote M1 to M2 transformation, 10 and induce myelogenous cells to differentiate into MDSCs. 11 Moreover, endothelial cells, cancer-associated fibroblasts (CAF), and pancreatic stellate cells in PDAC stroma as well as hypoxia and metabolic reprogramming induced by strong interstitial reactions are all involved in the formation of an immunosuppressive microenvironment.…”