LABORATORY OF
CELL STRESS & IMMUNITY

However, in the context of diseases such as cancer, this stress-immunity cycle may become dysregulated since cancer cells manipulate various components of this cycle to fuel their own growth at the expense of the tissue and the organism (see Figure 1). Broadly speaking, on one hand, cancer cells dysregulate the normal cellular stress responses to re-orient them towards upholding cellular growth, while inhibiting cell death and enabling invasive or metastatic behaviour. On the other hand, cancer cells and the tumour severely dysregulate or inhibit various components of the immune system, both locally in the tumour as well as systemically, thereby compromising the ability of the immune cells to ameliorate the dysregulation of cellular stress responses (Figure 1). Accordingly, inhibition of cancer cell death, stress-signalling driven growth, immunosuppressive tumour immune landscape (especially anti-inflammatory macrophages), and induction of CD8+T cell dysfunction or hypofunction, are only a few of the many different processes that cancer cells exploit to disturb the cellular stress-immunity cycle to facilitate tumour growth and dissemination (Figure 1).

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In fact, dysregulation of a homeostatic cellular stress-immunity process at multiple levels leads to a diversity of different CD8+T cell hypofunctional states - a concept our lab has championed over the last few years and also pioneered for the first time as a unified immunological model (Figure 2). Indeed, homeostatic T cell immunity with a successful outcome in terms of tumour amelioration consists of ten successive steps (Figure 2). Step 1: the presence of tumour-specific antigens in cancer cells; step 2: immunogenic uptake of these antigens by antigen-presenting cells (APCs); step 3: homing of antigen-primed and stimulated APCs towards lymphoid organs; step 4: antigen priming and co-stimulation of naive T cells by these activated APCs; step 5: expansion of antigen-specific effector T cells; step 6: the trafficking of these effector T cells out of the lymphoid organs towards the tumour tissue; and step 7: the infiltration of these T cells into the tumour. Once inside the tumour tissue, these T cells are likely to encounter various tumour-specific immuno-inhibitory pressures and spatial barriers (step 8). These include chronic inflammation (capable of recruiting bystander T cells via chemokine gradients), dysregulated microbial activity (in organs with microbial burdens), wound healing, dysregulated stroma, myeloid cells or vasculature, immune checkpoint signalling and other immunoregulatory mechanisms. After overcoming these barriers, T cells can contact cancer cells presenting cognate antigens (step 9). Finally, contingent on a productive interaction between antigen-presenting MHC class I molecules and T cell receptors, as well as susceptibility of the cancer cell to T cell-mediated cytotoxicity, the effector-cytotoxic T cells can eliminate the cancer cells (step 10; Figure 2).

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However, in the case of non-favourable disease outcome, for example, chronic viral infection or cancer; this disease-targeting immunity is dysregulated on various levels (indicated by red crosses; Figure 2), thereby leading to a diversity of hypofunctional T cell states. For instance, absence of clear tumour-specific antigens or tolerogenic uptake of cancer cells (failure of step 1 or 2) leads to tolerization, lack of co-stimulatory antigen presentation (failure of step 4) leads to anergy, inability of T cells to infiltrate the tumour tissue (failure of step 7) leads to T cell exclusion, chronic sensitization of T cells to antigens together with a hostile or stressful tumour microenvironment (overexposure to step 8) causes T cell exhaustion, and finally lack of tangible antigen presentation by cancer cells (failure of step 9) causes ignorance of tumour tissue. Immunity may also fail if cancer cells mount cell death resistance against T cell-associated cytotoxicity. Finally, some of these T cell states may culminate in dying, senescent or other terminally dysfunctional states under chronic stress in a tumour microenvironment, driven by dysregulation of T cell metabolism, depletion of pro-T cell mitogens and/or facilitators of T cell death (Figure 2).

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Conventional anticancer therapies have all strived to correct these dysregulations of the stress-immunity cycle by killing cancer cells and reduce tumour burden. Unfortunately, in past, these conventional anticancer therapies have achieved limited success in meaningfully prolonging the survival of patients. This is due to both primary and acquired resistance of cancer cells against these therapies as well as their inability to properly re-activate our immune system against (residual) cancer cells. However, a tremendous success in the pursuit to prolong cancer patient’s long-term survival has been achieved over the last decade, due to the development of cancer immunotherapy. Several immunotherapies are now available to clinicians and several more are in development. These include antibody-based, T cell-based, and vaccine-based therapies. Although such approaches have had great successes yet not all cancer patients or cancer types respond to current immunotherapies. This indicates that we still lack sufficient understanding of the tumoral dysregulation of stress-immunity cycle and its immunotherapeutic or cancer cell-level therapeutic vulnerabilities.

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Our CSI Lab aims to comprehensively dissect this cellular stress-immunity cycle, in order to understand its homeostatic as well as dysregulated "avatars". Our lab aims to exploit this knowledge to improve immunotherapy of hard-to-treat cancer types (e.g., brain cancer, colorectal cancer, kidney cancer), guided by high precision immune-biomarkers.