Immune checkpoint inhibitors (ICIs) have improved the survival of patients with non-small cell lung cancer (NSCLC) by reinvigorating tumor-specific T cell responses. However, the specificity of... Show moreImmune checkpoint inhibitors (ICIs) have improved the survival of patients with non-small cell lung cancer (NSCLC) by reinvigorating tumor-specific T cell responses. However, the specificity of such T cells and the human leukocyte antigen (HLA)-associated epitopes recognized, remain elusive. In this study, we identified NSCLC T cell epitopes of recently described NSCLC-associated antigens, termed keratinocyte differentiation antigens. Epitopes of these antigens were presented by HLA-A 03:01 and HLA-C 04:01 and were associated with responses to ICI therapy. Patients with CD8(+) T cell responses to these epitopes had improved overall and progression-free survival. T cells specific for such epitopes could eliminate HLA class I-matched NSCLC cells ex vivo and were enriched in patient lung tumors. The identification of novel lung cancer HLA-associated epitopes that correlate with improved ICI-dependent treatment outcomes suggests that keratinocyte-specific proteins are important tumor-associated antigens in NSCLC. These findings improve our understanding of the mechanisms of ICI therapy and may help support the development of vaccination strategies to improve ICI-based treatment of these tumors. Show less
Zanden, S.Y. van der; Luimstra, J.J.; Neefjes, J.; Borst, J.; Ovaa, H. 2020
Cancer immunotherapy has proven remarkably successful through instigation of systemic antitumor T cell responses. Despite this achievement, further advancements are needed to expand the scope of... Show moreCancer immunotherapy has proven remarkably successful through instigation of systemic antitumor T cell responses. Despite this achievement, further advancements are needed to expand the scope of susceptible cancer types and overcome variation in treatment outcomes between patients. Small-molecule drugs targeting defined pathways and/or cells capable of immune modulation are expected to substantially improve efficacy of cancer immunotherapy. Small-molecule drugs possess unique properties compatible with systemic administration and amenable to both extracellular and intracellular targets. These compounds can modify molecular pathways to overcome immune tolerance and suppression towards effective antitumor responses. Here, we provide an overview of how such effects might be achieved by combining immunotherapy with conventional and/or new small-molecule chemotherapeutics. Show less
The two branches of our highly advanced immune system work closely together to detect and eliminate pathological threats. The first line of defense is provided by the innate immune system via... Show moreThe two branches of our highly advanced immune system work closely together to detect and eliminate pathological threats. The first line of defense is provided by the innate immune system via detection of pathogenic or tumor cell fragments. Adaptive immune cells, on the other hand, recognize pathogens or malignant cells more specifically by scanning peptides, small protein fragments, presented by MHC molecules on other cells in our body. Specialized white blood cells (cytotoxic or killer T cells) can distinguish self- from non-self-peptides and directly eliminate cells that display signs of infection or mutation.The work described in this dissertation highlights how adaptive immunity can be used to our advantage, either from a therapeutic or diagnostic perspective. Immunotherapies that induce or promote anti-tumor or anti-viral responses have proven efficacious against infection and cancer. One strategy described is the development of chemically-modified epitopes as peptide vaccines, but small-molecule chemical drugs are also playing an increasing role in the field of cancer immunotherapy.In addition, monitoring of immune status and response to treatment, as well as mapping of epitopes, can aid diagnosis and design of treatment plans. The second part describes a novel method and application to visualize and monitor cytotoxic T cells. Show less
