Immune checkpoint inhibitors unleash pathogenic immune responses against the microbiota

Hu, Zishuo Ian; Link, Verena M.; Lima-Júnior, Djalma S.; Delaleu, Jérémie; Bouladoux, Nicolas; Han, Seong-Ji; Collins, Nicholas; Belkaid, Yasmine

doi:10.1073/pnas.2200348119

Cited by 34 publications

(34 citation statements)

References 91 publications

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“…One additional factor that might be shaping the T RM cell pool primarily is microbial antigen presentation, which is particularly important in barrier organs such as skin and intestine. In a mouse model, novel commensals in combination with ICB triggered a T cell–mediated irAE dermatitis, with the vast majority of the bacteria-specific T cells being T RM cells ( 23 ).…”

Section: Discussionmentioning

confidence: 99%

Checkpoint Blockade–Induced Dermatitis and Colitis Are Dominated by Tissue-Resident Memory T Cells and Th1/Tc1 Cytokines

Reschke

Shapiro

et al. 2022

Cancer Immunology Research

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Immune checkpoint blockade is therapeutically successful for many patients across multiple cancer types. However, immune-related adverse events (irAE) frequently occur and can sometimes be life-threatening. It is critical to understand the immunologic mechanisms of irAEs with the goal of finding novel treatment targets. Herein, we report our analysis of tissues from patients with irAE dermatitis using multiparameter immunofluorescence (IF), spatial transcriptomics, and RNA in situ hybridization (RISH). Skin psoriasis cases were studied as a comparison, as a known Th17-driven disease, and colitis was investigated as a comparison. IF analysis revealed that CD4+ and CD8+ tissue-resident memory T (TRM) cells were preferentially expanded in the inflamed portion of skin in cutaneous irAEs compared to healthy skin controls. Spatial transcriptomics allowed us to focus on areas containing TRM cells to discern functional phenotype and revealed expression of Th1-associated genes in irAE, compared to Th17-asociated genes in psoriasis. Expression of PD-1 and other inhibitory receptors was observed in irAE cases. RISH technology combined with IF confirmed expression of IFNγ, CXCL9, CXCL10, and TNFα in irAE dermatitis, as well as IFNγ within TRM cells specifically. The Th1-skewed phenotype was confirmed in irAE colitis cases compared to healthy colon.

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Section: Discussionmentioning

confidence: 99%

Checkpoint Blockade–Induced Dermatitis and Colitis Are Dominated by Tissue-Resident Memory T Cells and Th1/Tc1 Cytokines

Reschke

Shapiro

et al. 2022

Cancer Immunology Research

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“…Defining these pathways provides opportunities to develop specific therapeutic interventions. A recent study using preclinical models has shown that anti–CTLA-4 therapy activates microbiome-specific T cells in the skin ( 35 ). Therefore, it is also possible that the Trm population expanding in our patients is likely specific for gut microbial antigens.…”

Section: Discussionmentioning

confidence: 99%

Distinct pretreatment innate immune landscape and posttreatment T cell responses underlie immunotherapy-induced colitis

Nahar¹,

Marsh‐Wakefield²,

Rawson³

et al. 2022

JCI Insight

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Immune-related adverse events are a major hurdle to the success of immunotherapy. The immunological mechanisms underlying their development and relation to anti-tumour responses are poorly understood. By examining both systemic and tissue-specific immune changes induced by combination anti-CTLA-4 and anti-PD-1 immunotherapy, we found distinct repertoire changes in patients who developed moderate-severe colitis irrespective of their anti-tumour response to therapy. The proportion of circulating monocytes were significantly increased at baseline in patients who subsequently developed colitis compared to patients who did not develop colitis and biopsies from patients with colitis showed monocytic infiltration of both endoscopically and histopathologically normal and inflamed regions of colon. The magnitude of systemic expansion of T cells following commencement of immunotherapy was also greater in patients who developed colitis. Importantly, we show expansion of specific T cell subsets within inflamed regions of the colon, including tissueresident memory CD8+ T cells and Th1 CD4+ T cells in patients who developed colitis. Our data also suggest that CD8+ T cell expansion was locally induced, while Th1 cell expansion was systemic. Together our data show exaggerated innate and T cell responses to combination immunotherapy synergise to propel colitis in susceptible patients.

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“…Hence, more work is needed to sort out their exact role in patients with low IL-2 ( Gaborit et al., 2020 ; Gao et al., 2022 ). Similarly, IL-17-producing T cells that are associated with hyperactive and pathogenic immune responses are induced in the presence of commensals such as staphylococcal species specifically upon the use of immune checkpoint inhibitors ( Hu et al., 2022 ). This raised concerns over whether all commensal-specific immune responses are pathogenic in the context of anti-tumor therapy and how cancer patients would fare on Th17 stimulating vaccines.…”

Section: Immune Dysfunctions Imposed By S Aureusmentioning

confidence: 99%

Staphylococcus aureus adaptive evolution: Recent insights on how immune evasion, immunometabolic subversion and host genetics impact vaccine development

Lung

Chan

Prince

et al. 2022

Front. Cell. Infect. Microbiol.

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Despite meritorious attempts, a S. aureus vaccine that prevents infection or mitigates severity has not yet achieved efficacy endpoints in prospective, randomized clinical trials. This experience underscores the complexity of host-S. aureus interactions, which appear to be greater than many other bacterial pathogens against which successful vaccines have been developed. It is increasingly evident that S. aureus employs strategic countermeasures to evade or exploit human immune responses. From entering host cells to persist in stealthy intracellular reservoirs, to sensing the environmental milieu and leveraging bacterial or host metabolic products to reprogram host immune responses, S. aureus poses considerable challenges for the development of effective vaccines. The fact that this pathogen causes distinct types of infections and can undergo transient genetic, transcriptional or metabolic adaptations in vivo that do not occur in vitro compounds challenges in vaccine development. Notably, the metabolic versatility of both bacterial and host immune cells as they compete for available substrates within specific tissues inevitably impacts the variable repertoire of gene products that may or may not be vaccine antigens. In this respect, S. aureus has chameleon phenotypes that have alluded vaccine strategies thus far. Nonetheless, a number of recent studies have also revealed important new insights into pathogenesis vulnerabilities of S. aureus. A more detailed understanding of host protective immune defenses versus S. aureus adaptive immune evasion mechanisms may offer breakthroughs in the development of effective vaccines, but at present this goal remains a very high bar. Coupled with the recent advances in human genetics and epigenetics, newer vaccine technologies may enable such a goal. If so, future vaccines that protect against or mitigate the severity of S. aureus infections are likely to emerge at the intersection of precision and personalized medicine. For now, the development of S. aureus vaccines or alternative therapies that reduce mortality and morbidity must continue to be pursued.

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Immune checkpoint inhibitors unleash pathogenic immune responses against the microbiota

Cited by 34 publications

References 91 publications

Checkpoint Blockade–Induced Dermatitis and Colitis Are Dominated by Tissue-Resident Memory T Cells and Th1/Tc1 Cytokines

Checkpoint Blockade–Induced Dermatitis and Colitis Are Dominated by Tissue-Resident Memory T Cells and Th1/Tc1 Cytokines

Distinct pretreatment innate immune landscape and posttreatment T cell responses underlie immunotherapy-induced colitis

Staphylococcus aureus adaptive evolution: Recent insights on how immune evasion, immunometabolic subversion and host genetics impact vaccine development

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