Immune recognition of cancer

Our research ambition is to dissect how the human immune system can recognize cancer cells, and how such recognition can be strengthened for therapeutic purposes. To achieve this goal we employ a technology-driven approach, in which novel assay systems are designed that can be used to determine how tumor-specific immune responses develop and are regulated. This technological toolbox is then exploited to reveal the mode of action of clinically used immunotherapies and to design more specific and more effective immune interventions.

What T cells see on human cancer
The ability of T cells to distinguish cancer cells from healthy body cells is an obvious conditio sine qua non for effective T cell-based cancer immunotherapies. However, for many years the molecular basis of such selective recognition has remained a matter of dispute. We have previously set out to shed light on this issue through the design of technologies for high-througput analysis of antigen reactivity of both cytotoxic (CD8) and helper (CD4) T cells. In subsequent work, we have used these technologies to demonstrate that T cell reactivity against the neoantigens that arise as a consequence of DNA damage is present in a large fraction of tumors with high mutational burdens, such as melanoma. Furthermore, we have demonstrated that such T cell recognition of neoantigens can be boosted by both immune checkpoint blockade and TIL therapy. Together, this work has provided significant evidence that the activity of therapies that boost endogenous tumor-specific T cell responses relies to a substantial extent on neoantigen recognition. Furthermore, the observed relationship between tumor mutational burden and response to immune checkpoint blockade observed by others and us provides additional support for this model.
With the now widespread evidence for a dominant role of cancer neoantigens in T cell control of cancer, a next challenge will be to devise clinically applicable strategies to selectively boost neoantigen-specific T cell reactivity (see Haanen lab).
Selected reading: Toebes, Nat Med 2006; Hadrup, Nat Methods 2009; van Rooij, J Clin Oncol 2013; Rizvi, Science 2015; Linnemann, Nat Med 2015; Verdegaal, Nature 2016; Schumacher Ann Rev Immunol 2019

Video describing T cell recognition of cancer and role of immune checkpoint blockade.

Checkpoints in immune function
In the significant subset of human cancers in which en endogenous immune response develops (see above), the ability of the immune system to control cancer outgrowth is capped by a series of inhibitory mechanisms that include T cell checkpoint molecules such as PD-1 and CTLA-4, but also signaling through inhibitory cytokine receptors and metabolic checkpoints. We have set out to identify such regulators of (intratumoral) immune activity through genetic screening. In prior work, this has resulted in the identification of CMTM6 as a molecular partner of the PD-L1 T cell checkpoint and QPCTL as a post-translational modifier of the CD47 myeloid cell checkpoint. Furthermore, we’ve demonstrated that inhibition of QPCTL activity forms a conceptually attractive strategy to promote control of tumor cells by macrophages and neutrophils. In ongoing genetic screens we hope to uncover additional regulators of the activity of both T cell and myeloid cell activity.
Selected reading: Mezzadra, Nature 2017; Sun, Immunity 2019; Logtenberg, Nat Med 2019; Logtenberg, Immunity 2020

Inner workings of the T cell-based immune system
To properly understand pathophysiology, a detailed understanding of physiological cell and tissue behavior is critical. By the same token, to understand T cell dysfunction in cancer, we need to understand the formation of protective T cell responses during natural immune responses. Our approach to dissect physiological T cell responses has been the design of assay systems that can be used to measure cellular descent and kinship, and – more recently – replicative history in vivo. In prior work we have developed and exploited the concept of cellular barcoding to reveal in vivo immune cell behavior at the single cell level. More recent work in this area focusses on the descent of tissue-resident memory T cells, and on the identification of memory T cell populations with disparate replicative histories that predict cell potential upon renewed antigen encounter.
Selected reading:van Heijst, Science 2009; Naik, Nature 2013; Gerlach, Science 2013; Perié, Cell 2015; Dijkgraaf, Nat Immunol 2019; Hoekstra, Nat Cancer 2020; Kok, JEM in press.

Video describing generation of pMHC complexes through UV-induced ligand exchange.

Novel technologies
With the explosion of immuntherapeutic interventions in cancer patients, the development of technological platforms that can be utilized to extract an increasing amount of information from human material has become of major importance. Following our prior development of MHC-based technologies, we’ve over the past years invested in technology that can be used to understand T cell (dys)function at human tumor sites. Specifically, we’ve developed technology for the high-throughput profiling of (tumor) antigen reactivity of intratumoral TCRs, providing a means to measure the intrinsic tumor recognition potential of different T cell populations in a manner that is not confounded by T cell state. In addition, in an effort led by Daniela Thommen we’ve developed a system to perturb human tumor sites ex vivo, providing a means to dissect how clinically used immunotherapies alter immune cell activity at the tumor site with an unprecedented temporal resolution. An emerging interest in this research area is the development of datasets that may be utilized to predict TCR specificity, a capacity that would be of major diagnostic and therapeutic value.
Selected reading: Scheper, Nat Med 2019; van der Leun, Cell 2019; van der Leun, Nat Rev Cancer 2020

Neoadjuvant immune checkpoint blockade
The Netherlands Cancer Institute is special in its capacity to bring biomedical researchers and medical oncologists together. Together with Christian Blank we designed the first clinical study to evaluate the immune activating potential of neoadjuvant versus adjuvant immune checkpoint blockade (ICB). The data obtained have provided strong evidence for the potential clinical value of neoadjuvant ICB, a notion that has subsequently been confirmed by Blank and other NKI clinical investigators in a series of cancer types.
Selected reading: Blank, Nat Med 2018; Chalabi, Nat Med 2020

Immune recognition of cancer

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