Unleashing the immune response to NY-ESO-1 cancer testis antigen as a potential target for cancer immunotherapy

Abstract

Introduction: Cancer Immunotherapy has recently emerged as a promising and effective modality to treat different malignancies. Antigenic profiling of cancer tissues and determination of any pre-existing immune responses to cancer antigens may help predict responses to immune intervention in cancer. NY-ESO-1, a cancer testis antigen is the most immunogenic antigen to date. The promise of NY-ESO-1 as a candidate for specific immune recognition of cancer comes from its restricted expression in normal adult tissue but frequent occurrence in multiple tumors including melanoma and carcinomas of lung, esophageal, liver, gastric, prostrate, ovarian, and bladder.

Main body: This review summarizes current knowledge of NY-ESO-1 as efficient biomarker and target of immunotherapy. It also addresses limitations and challenges preventing a robust immune response to NY-ESO-1 expressing cancers, and describes pre-clinical and clinical observations relevant to NY-ESO-1 immunity, holding potential therapeutic relevance for cancer treatment.

Conclusion: NY-ESO-1 induces strong immune responses in cancer patients but has limited objective clinical responses to NY-ESO-1 expressing tumors due to effect of competitive negative signaling from immune-checkpoints and immune-suppressive tumor microenvironment. We propose that combination therapy to increase the efficacy of NY-ESO-1 specific immunotherapeutic interventions should be explored to unleash the immune response against NY-ESO-1 expressing tumors.

Keywords: Cancer immunotherapy; Cancer testis antigen; Cancer vaccine; Immune checkpoint inhibitors; NY-ESO-1; Tumor microenvironment.

Fig. 1

Schematic representation of amino acids representing immunogenic epitopes against anti-NY-ESO-1 antibody, CD4+ and CD8+ T cell responses. Naturally occurring anti-NY-ESO-1 antibodies are mostly mapping to soluble N-terminus region while the cellular responses are mapping to the C-terminus region [139]

Fig. 2

Cancer Immunotherapeutic strategies targeting NY-ESO-1 antigen. a NY-ESO-1 exhibits the capacity to induce a strong natural anti-NY-ESO-1 antibody, CD4 + and CD8 + T cell responses in an integrated manner. Effective tumor control against NY-ESO-1 expressing tumors is compromised due to strong interplay of the immune checkpoint inhibitory molecules such as programmed death 1 [PD-1], programmed death-ligand 1 [PDL-1], cytotoxic T-lymphocyte-associated protein 4 [CTLA-4] and other immune-suppressive tumor microenvironment cells such as regulatory T cells (TREG) and myeloid-derived suppressor cells (MDSC). In the presence of these immune inhibitory and immune suppressive cells, high titers of anti-NY-ESO-1 antibodies are observed while the anti-NY-ESO-1 T cell responses become ineffective. This leads to limited objective clinical responses to control tumors. b To strengthen the induction of effective anti-NY-ESO-1 specific CD4 + and CD8 + T cell immune responses and to reverse immunosuppression, various immune-modulation strategies including anti-PD-1, anti-PDL-1, anti-CTLA-4 blocking antibodies, TREG and MDSC depletion, NY-ESO-1 immune complex/dendritic cells (DC) vaccine, anti-NY-ESO-1 chimeric antigen receptor T cells (CAR T), either alone or in combination with standard of care therapies such as radiotherapy and chemotherapy can be designed for enhanced anti-NY-ESO-1 T cells responses leading to effective tumor eradication and a successful clinical response