An intra-tumoral niche maintains and differentiates stem-like CD8 T cells

Jansen, Caroline S.; Prokhnevska, Nataliya; Master, Viraj A.; Sanda, Martin G.; Carlisle, Jennifer W; Bilen, Mehmet Asım; Cardenas, Maria A; Wilkinson, Scott; Lake, Ross; Sowalsky, Adam G.; Valanparambil, Rajesh M.; Hudson, William Henry; McGuire, Donald J.; Melnick, Kevin; Khan, Alamzeb; Kim, Kyu; Chang, Yun Min; Kim, Alice; Filson, Christopher P.; Alemozaffar, Mehrdad; Osunkoya, Adeboye O.; Mullane, Patrick; Ellis, Carla LaShannon; Akondy, Rama; Im, Se Jin; Kamphorst, Alice O.; Reyes, Adriana Moon; Liu, Yuan; Kissick, Haydn

doi:10.1038/s41586-019-1836-5

Cited by 605 publications

(569 citation statements)

References 38 publications

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“…In CD8+ T cells, CD8+ PD-1+TIM-3− cells were reported to contain stem-like CD8 T cells with higher proliferative potential. This study supposed that stem-like CD8 T cells might be more abundant in the lower-grade tumours though we couldn't evaluate in this study 8 . In CD4 T cells, Yang et al reported the presence of heterogeneity of PD-1-expressing CD4 T cells and identified a functionally antithetical population within CD4 T cells expressing PD-1 in follicular lymphoma 28 .…”

Section: Discussionmentioning

confidence: 85%

Tumour grade significantly correlates with total dysfunction of tumour tissue-infiltrating lymphocytes in renal cell carcinoma

Kawashima

Kanazawa

Kidani

et al. 2020

Sci Rep

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It is important to evaluate the clinical importance of both CD8 T cells and CD4 T cells expression simultaneously because they have crucial networks in tumour targeting immune responses. In 97 RCC patients, RNA sequencing and gene set enrichment analysis of both CD8 and CD4 T cells based on the expression levels of PD-1 and TIM-3 implied that the populations of PD-1+TIM-3+ CD8 T cells and PD-1lowTIM-3 + CD4 T cells were characterized as exhausted CD8 T cells and regulatory CD4 T cells, respectively. These populations of CD4 and CD8 T cells were significantly upregulated in the patients with RCC of higher WHO/ISUP grade (grades 3, 4) (P < 0.001). Moreover, the cytokine productivities of each population in both CD4 and CD8 T cells of the higher-grade patients were significantly lower than those of the lower-grade patients (P < 0.05). Multivariate analysis showed the prognosis of patients with metastatic RCC of higher WHO/ISUP grade treated by nivolumab to be significantly worse than that of patients with lower grade (P = 0.026). This study showed that tumour grade significantly correlated with dysfunction of both CD4+ and CD8+ TILs and the efficacy of nivolumab treatment. Recently, cancer immunotherapy including monotherapy 1 or combination therapy with anti-PD-1 antibody 2 showed better therapeutic effect than molecular-targeted therapies for metastatic renal cell carcinoma (RCC) patients. However, the therapeutic effect of anti-PD-1 antibody monotherapy against RCC is limited, and both the establishment of biomarkers to predict efficacy and the development of new therapeutic target factors are necessary using tissue infiltrating lymphocytes (TILs). Recently, subpopulations of CD4 and CD8 T cells stratified by PD-1 expression in the tumour microenvironment were reported to be important prognostic factors in cancer immunotherapy 3-5. The transcriptomic data of TILs were published based not only on a single cell 6,7 but also on the intensity of PD-1 expression 3 , and high expression of PD-1 was identified as a predictive marker in non-small cell lung cancer patients. Analysis of TILs according to the expression pattern of multiple immunocheckpoint (IC) molecules revealed the presence of terminally differentiated and stem like CD8 T cells in RCC patients 8. However, few studies have simultaneously evaluated the functions of both CD8 T cells and CD4 T cells, which have crucial networks in establishing immune status in tumour microenvironments 9 and tumour targeting immune responses 10-12 .

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Section: Discussionmentioning

confidence: 85%

Tumour grade significantly correlates with total dysfunction of tumour tissue-infiltrating lymphocytes in renal cell carcinoma

Kawashima

Kanazawa

Kidani

et al. 2020

Sci Rep

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“…We observed reduced in ltration of lymphocytes in KDM6Amutated tissues, including neutrophils, macrophages, and CD8 + T cells, which is consistent with previous reports showing that these immune cells play key roles in the tumour microenvironment and suppress the immune response. A reduced number of CD8 + T cells in the tumour indicated a worse prognosis for patients in a previous study [20]. GSEA of Kyoto Encyclopedia of Genes and Genomes pathways between gene sets of BC samples with mutated and wild-type KDM6A demonstrated that the signalling pathways of cell-adhesion molecules, ECM receptor interaction, and focal adhesion were also suppressed by KDM6A mutation.…”

Section: Discussionmentioning

confidence: 72%

Significance of KDM6A Mutation in Bladder Cancer Immune Escape

Chen

Lin

Pang

et al. 2020

Preprint

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Background: Bladder cancer (BC) is the fourth most prevalent neoplasm in men and is associated with high tumour recurrence rates, leading to major treatment challenges. Lysine-specific demethylase 6A (KDM6A) is frequently mutated in several cancer types; however, its effects on tumour progression and clinical outcome in BC remain unclear. Here, we explored the potential role of KDM6A in regulating the antitumor immune response. Methods: We mined The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases for somatic mutation and clinical data in patients with BC. Results: We found frequent mutations in 12 genes in both cohorts, including TP53, KDM6A, CSMD3, MUC16, STAG2, PIK3CA, ARID1A, RB1, EP300, ERBB2, ERBB3, and FGFR3. The frequency of KDM6A mutations in the TCGA and ICGC datasets was 25.97% and 24.27%, respectively. In addition, KDM6A mutation was associated with a lower number of tumour-infiltrating lymphocytes and indicated a state of immune tolerance. KDM6A mutation was associated with lower KDM6A expression level compared with that in samples carrying the wild-type gene. Further, survival analysis showed that the prognosis of patients with low KDM6A expression was worse than that with high KDM6A expression. Using the CIBERSORT algorithm, Tumor Immune Estimation Resource site, and Gene Set Enrichment Analysis, we found that KDM6A mutation downregulated nine signalling pathways that participate in the immune system and attenuated the tumour immune response. Conclusion: Overall, we conclude that KDM6A mutation is frequent in BC and promotes tumour immune escape, which may serve as a novel biomarker to predict the immune response. Key Words: KDM6A, bladder cancer, mutation, immune

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“…Progenitor exhausted CD8 + TILs, as defined by their stem-like genetic profile ( i.e. Tcf1/ Tcf7 ) with relatively little to no expression of checkpoint receptors, have the potential to proliferate and give rise to effector-like cells, particularly in response to anti-PD1 therapy 10,24–30 . Given that Tcf1/ Tcf7 plays a critical role in orchestrating a progenitor exhausted fate while antagonizing an effector program at the early stage of CD8 + T cell differentiation 11 , we postulated that male bias in Tcf7 gene expression for clusters 1 and 9, as well as in the frequency of Tcf7 -enriched clusters 2 and 7, may indicate development of progenitor exhausted CD8 + TILs.…”

Section: Cd8+ T Cell Immunity Is Required For Sex Differences In Murimentioning

confidence: 99%

Distinct CD8⁺T Cell Programming in the Tumor Microenvironment Contributes to Sex Bias in Bladder Cancer Outcome

Kwon¹,

Chung²,

Kaneko³

et al. 2020

Preprint

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Disclosure of Potential Conflicts of Interest: No potential conflicts of interest were disclosed. 24Abstract: Men and women show striking yet unexplained discrepancies in 25 incidence, clinical presentation, and therapeutic response across different types of 26 infectious/autoimmune diseases and malignancies 1,2 . For instance, bladder cancer 27 shows a 4-fold male-biased incidence that persists after adjustment for known risk 28 factors 3,4 . Here, we utilize murine bladder cancer models to establish that male-biased 29 tumor burden is driven by sex differences in endogenous T cell immunity. Notably, sex 30 differences exist in early fate decisions by intratumoral CD8 + T cells following their 31 activation. While female CD8 + T cells retain their effector function, male counterparts 32 readily adopt a Tcf1 low Tim3progenitor state that becomes exhausted over tumor 33 progression. Human cancers show an analogous male-biased frequency of exhausted 34 CD8 + T cells. Mechanistically, we describe an opposing interplay between CD8 + T cell 35 intrinsic androgen and type I interferon 5,6 signaling in Tcf1/Tcf7 regulation and formation 36 of the progenitor exhausted T cell subset. Consistent with female-biased interferon 37 response 7 , testosterone-dependent stimulation of Tcf1/Tcf7 and resistance to interferon 38 occurs to a greater magnitude in male CD8 + T cells. Male-biased predisposition for CD8 + 39T cell exhaustion suggests that spontaneous rejection of early immunogenic bladder 40 tumors is less common in males and carries implications for therapeutic efficacy of 41 immune checkpoint inhibitors 8,9 . 42Main: Sex is a biological variable with significant influence on immune function 1 . 43However, mechanisms underlying sex-biased incidence and mortality of various cancers 44 arising in non-reproductive organs remain elusive 2 . Indeed, bladder cancer shows a 4-45 fold male-biased incidence globally, which cannot be explained by established risk 46 factors: smoking, exposure to occupational hazards and urinary tract infection 3,4 . Here, 48 largely mediated by sex differences in T cell immunity. Flow cytometric and single cell 49 RNA-seq analyses of CD8 + tumor-infiltrating leukocytes (TILs) identified a striking male 50 bias in the formation of Tcf1 low Tim3progenitor cells 10 and in their transition to a 51 hypofunctional Tcf1 -Tim3 + exhausted state upon prolonged stimulation. In particular, 52androgen signaling was enriched in the progenitor exhausted subset. We found that 53 testosterone-induced Tcf1, an early molecular orchestrator of an exhaustion-associated 54 transcriptional landscape 11 in male CD8 + T cells, is also more resistant to pertinent 55 repression by female-biased type I interferon signaling 5 . Collectively, these findings 56 highlight sex differences in intratumoral CD8 + T cell fate as a potential mechanism 57 underlying bladder cancer sex bias and identify androgen as a possible target to modulate 58 CD8 + TIL exhaustion. 59CD8 + T cell immunity is required for sex differences in murine...

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An intra-tumoral niche maintains and differentiates stem-like CD8 T cells

Cited by 605 publications

References 38 publications

Tumour grade significantly correlates with total dysfunction of tumour tissue-infiltrating lymphocytes in renal cell carcinoma

Tumour grade significantly correlates with total dysfunction of tumour tissue-infiltrating lymphocytes in renal cell carcinoma

Significance of KDM6A Mutation in Bladder Cancer Immune Escape

Distinct CD8⁺T Cell Programming in the Tumor Microenvironment Contributes to Sex Bias in Bladder Cancer Outcome

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An intra-tumoral niche maintains and differentiates stem-like CD8 T cells

Cited by 605 publications

References 38 publications

Tumour grade significantly correlates with total dysfunction of tumour tissue-infiltrating lymphocytes in renal cell carcinoma

Tumour grade significantly correlates with total dysfunction of tumour tissue-infiltrating lymphocytes in renal cell carcinoma

Significance of KDM6A Mutation in Bladder Cancer Immune Escape

Distinct CD8+T Cell Programming in the Tumor Microenvironment Contributes to Sex Bias in Bladder Cancer Outcome

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Distinct CD8⁺T Cell Programming in the Tumor Microenvironment Contributes to Sex Bias in Bladder Cancer Outcome