Expanding Roles for CD4 T Cells and Their Subpopulations in Tumor Immunity and Therapy

Abstract

The importance of CD4 T cells in orchestrating the immune system and their role in inducing effective T cell-mediated therapies for the treatment of patients with select established malignancies are undisputable. Through a complex and balanced array of direct and indirect mechanisms of cellular activation and regulation, this functionally diverse family of lymphocytes can potentially promote tumor eradication, long-term tumor immunity, and aid in establishing and/or rebalancing immune cell homeostasis through interaction with other immune cell populations within the highly dynamic tumor environment. However, recent studies have uncovered additional functions and roles for CD4 T cells, some of which are independent of other lymphocytes, that can not only influence and contribute to tumor immunity but paradoxically promote tumor growth and progression. Here, we review the recent advances in our understanding of the various CD4 T cell lineages and their signature cytokines in disease progression and/or regression. We discuss their direct and indirect mechanistic interplay among themselves and with other responding cells of the antitumor response, their potential roles and abilities for “plasticity” and memory cell generation within the hostile tumor environment, and their potentials in cancer treatment and immunotherapy.

Permissive/Protective Interplay of Microbiota with T Cell Adaptive Immune Response in Colon Cancer

“…An effective anti-tumor immune response is generated by both CD4+ and CD8+ T cells and their interactions; also, CD4+ Th1 cells induce tumor-specific CD8+ T cells (52)(53)(54). As the study of human colon cancer samples has confirmed, Th1 adaptive immunity and presence of tumorspecific cytotoxic CD8+ cells are associated with better clinical outcomes and less tumor recurrence (55,56).…”

Low-dose cyclophosphamide depletes circulating naïve and activated regulatory T cells in malignant pleural mesothelioma patients synergistically treated with dendritic cell-based immunotherapy

“…16 For an effective anti-tumor immune response, both a CD4 and CD8 T cell response is required, which can be enhanced by immune checkpoint blockade. 17 By loading them ex vivo with tumor antigens, they can be used as cellular immune therapy. DC-based immunotherapy is, in contrast to other immunotherapies including adoptive T cell transfer and peptide-based vaccines, not human lymphocyte antigen (HLA)-restricted and can induce an immune response to a wide array of antigens.…”

Towards tumor immunodiagnostics

“…The acquisition of CD4 occurs in the thymus and is retained by the naïve CD4+ T cells that migrate to the secondary lymphoid organs, as well as by the various effector T cell subpopulations developing thereafter (49). Depending on the cytokine milieu at the site of the activation of the CD4+ naïve T cell, different subpopulations of CD4+ T cells will be produced.…”

“…These cell populations in concert exert a tumor elimination effect. Under the effect of IL-4, STAT-6 activation and the transcription factor GATA-3 drive the Th2 cell differentiation (49). Th2 lymphocytes produce primarily IL-4 and IL-5 and drive a humoral immune response and chemotaxis for eosinophils in the site of the tumor.…”

“…CD4+ Tfh cells are present within the follicular germinal centers and in TLSs related to the tumors. They express the transcription factor BCL-6, PD-1, CXCR5 and molecules important for B cell development (49).…”