Inherent CD40L Expression Complements CD8⁺ T Cell Dependent Anti-Tumor Immunity

Adoptive T cell therapy with tumor-specific CD8⁺ T cells is a promising treatment option for a variety of malignant diseases. However, it is unclear which subset of CD8⁺ T cells characterized by distinct functions is most suitable for achieving effective and durable anti tumor responses. So far CD8⁺ T cells have been considered to act predominantly as cytotoxic effector cells in cellular anti-tumor immunity. In this respect cytolytic molecules such as perforin and granzymes and apoptosis-inducing receptors of the tumor necrosis family such as FasL, TNFα and TRAIL have been regarded as major CD8⁺ T cell effector mechanisms.

We here demonstrate in an experimental tumor model that CD40L, the key molecule for “immunological help”, is expressed by up to 50% of tumor-specific CD8⁺ T cells in B6 mice challenged with SV40 T antigen⁺ cancer cells. To study the influence of CD40L on anti-tumor CD8⁺ T cell immunity in vivo we challenged Rag1^-/- mice with cancer cells and transferred wt or CD40L^-/- CD8⁺ T cells. Transfer of wt CD8⁺ T cells prevented the establishment of a solid tumor, whereas injection of CD40L^-/- CD8⁺ T cells alone or in addition with wt CD4⁺ T cells resulted in a non-controlled tumor development similar to non-treated tumors. The requirement of CD40L on CD8⁺ T cells for tumor rejection was further confirmed by injecting cancer cells in mice that lack CD40L expression only on mature CD8⁺ T cells. CD40L^flox x E8I^cre mice were more susceptible to tumor formation than wt mice. Furthermore we demonstrated that CD8⁺ T-cell derived CD40L had to interact with CD40 on cancer cells, an eminent signal to induce apoptosis in various cancer cell types.

Our results reveal a crucial functional relevance of CD40L expressed by CD8⁺ T cells in anti-tumor immunity. Various cancer cell types express CD40 and its engagement induces pro-apoptotic or growth-inhibitory signals in a variety of cancer cells. Therefore CD40 agonists are recognized as promising agents for therapeutic interventions. We here introduce CD40L⁺ CD8⁺ memory T cells as a new major physiological source of CD40L, essential for rejection of tumors. Our data reveal that the presence or absence of CD40L⁺ CD8⁺ T cells represents a crucial element in control of CD40 expressing cancers disclosing novel treatment approaches in adoptive T-cell therapies novel treatment approaches.

No relevant conflicts of interest to declare.