Regulation of cytotoxic T-Lymphocyte trafficking to tumors by chemoattractants: implications for immunotherapy

Abstract

Cancer immunotherapy has recently emerged as an important treatment modality. FDA approval of provenge, ipilimumab and pembrolizumab has started to deliver on the long awaited promise of cancer immunotherapy. Many new modalities of immunotherapies targeting cytotoxic T lymphocytes (CTLs) responses, such as adoptive cell therapies and vaccines, are in advanced clinical trials. In all these immunotherapies, migration of CTLs to the tumor site is a critical step for achieving therapeutic efficacy. However, inefficient infiltration of activated CTLs into established tumors is increasingly being recognized as one of the major hurdles limiting efficacy. Mechanisms that control migration of CTLs to tumors are poorly defined. In this review, the authors discuss the chemoattractants and their receptors that have been implicated in endogenous- or immunotherapy-induced CTL recruitment to tumors and the potential for targeting these pathways for therapeutic efficacy.

Keywords:

• anti-tumor immunity
• BLT1
• cancer
• cancer immune surveillance
• CD8⁺ T cells
• chemokine receptors
• chemokines
• CTL migration
• CXCR3
• leukotriene B4

Acknowledgements

The authors would like to thank JW Eaton for critical reading of the manuscript.

Financial & competing interest’s disclosure

All authors disclosed no potential conflict of interest. Research in the author’s laboratory has been supported by funding in part from the NIH R01 (CA138623), Kentucky Lung Cancer Research Program, The James Graham Brown Cancer Center and a grant from The University of Louisville School of Medicine.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Cancer harbors resistance mechanisms to restrict cytotoxic T lymphocyte (CTL) infiltration into tumors.

• On CTL activation, chemokine receptors, such as CXCR3, CCR5, CX3CR1 and BLT1, are intrinsically induced to facilitate the migration of these cells to tumors.

• CD4⁺ T-cell recruitment to tumors may also enhance infiltration, multiplication, survival and function of activated CTLs in tumor.

• Ectopic expression of chemokine receptors mediating CTL migration may facilitate CTL infiltration in tumors.

• Chemoattractants can be released at tumor sites to enhance CTL infiltration in various forms of immunotherapies or in combination therapies, such as chemoimmunotherapy and radioimmunotherapy to enhance therapeutic efficacy.

Notes