Tumor-Specific Cytotoxic T Cells Are Crucial for Efficacy of Immunomodulatory Antibodies in Patients with Lung Cancer

Abstract

There is growing evidence that activation of the immune system may be an effective treatment for patients with either small cell lung cancer or non-small cell lung cancer (NSCLC). Immunomodulatory antibodies directed against cytotoxic T cell-associated antigen 4 (CTLA-4/CD152) and programmed cell death ligand 1 (PDL1/ CD274) showed clinical efficacy in patients with lung cancer. The key immune cells responsible for antitumor activity are the CTLs. The presence of these tumor-directed CTLs, both in number and functionality, is a prerequisite for the immune system to attack cancer cells. Immunomodulatory agents attempt to increase the efficacy of CTL activity. Thus, the limited number of patients who benefit from immunomodulatory antibodies may be caused by either an inadequate number or the impairment of CTL activity by the hostile environment created by the tumor. In this review, we discuss tumor-induced impairment of CTLs and experimental treatments that can stimulate T-cell responses and optimize specific CTL function. We discuss 2 types of immune cells with known suppressive capacity on CTLs that are of pivotal importance in patients with lung cancer: regulatory T cells and myeloid-derived suppressor cells. Cancer Res; 73(8);

Adjuvant cellular immunotherapy in patients with resected primary non-small cell lung cancer

“…13 Clinical epidemiology also provides evidence to support the existence of antitumoral immune responses in some forms of cancer, including lung cancer, [8][9][10] which provided the rationale of CIT for the treatment of NSCLC. Indeed, previous studies have increasingly confirmed the positive clinical efficacy of CIT in the treatment of NSCLC.…”

“…In recent years, multiple studies have shown that cancer formation and progression in patients with NSCLC are particularly influenced by tumor immune responses, [8][9][10][11][12][13] indicating that immune-based therapy could be an effective treatment option for patients with NSCLC. Current approaches to activate the immune system focus on vaccination, such as dendritic cell vaccines to increase the frequency of tumor-specific cytotoxic T lymphocytes (CTLs) and adoptive transfer of immune effector cells to promote tumor regression.…”

The tumor immune microenvironment in octogenarians with stage I non-small cell lung cancer

“…However, patients 70 years of age are underrepresented in lung cancer clinical research trials 33,34 and the role of age-related immunosenescence in the efficacy of immunotherapies remains unclear. With recent results emphasizing number and functionality of tumor-infiltrating immune cells as a critical parameter in predicting the efficacy of immunomodulatory therapies, such as checkpoint inhibitors, 35 our findings are of translational importance. Our results support including older patients deemed fit for surgical resection in neoadjuvant or adjuvant immunotherapy trials for lung cancer.…”

The future of immune checkpoint blockade immunotherapy: towards personalized therapy or towards combination therapy

“…What can we offer for the majority of patients if their tumors are negative for expression of these checkpoint molecules, or are too few or lack of infiltration of CD4, CD8 T cells and NK cells, or even are positive for the expression of checkpoint molecules but are still resistant to current blockade therapy? In fact, immune impairment is commonly observed in cancer patients, such as impairment of T cells (19) and NK cells (20). To achieve an optimal clinical outcome for cancer patients, we believe that the future of immune checkpoint blockade therapy, or in general, cancer immunotherapy, should be towards personalized combination therapy with existing approaches, such as: therapeutic antibodies, antibody-drug conjugates, immune checkpoint blockades, CAR-T and NK cells, DCs, vaccines, oncolytic viruses, cytokines and/or depletion of immune suppressor cells like myeloid-derived suppressor cells (MDSC), regulatory T cells (Treg), tumor-associated macrophages (TAM), etc.…”