P09.05 Plasma CD27, a surrogate of intratumoral CD27-CD70 interaction, correlates with immunotherapy resistance in renal cancer
Nadine BenhamoudaIkuan SamNicolas EpaillardAlain GeyAntonin SaldmannJoséphine PineauMilena HasanVirginie VerkarreValentina LibriSébastien MellaClémence GranierChloé BroudinPatrice RavelBernd JablaNathalie ChaputLaurence AlbigèsYann VanoOlivier AdotéviStéphane OudardÉric Tartour
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Abstract:
Background
CD70, a costimulatory molecule on antigen presenting cells, is known to activate CD27-expressing T cells. CD27-CD70 interaction leads to the release of soluble CD27 (sCD27). However, persistent interaction of CD27 and CD70 such as in chronic infection may exhaust the T cell pool and promote apoptosis. Surprisingly, our analysis based on TCGA database show that clear cell renal cell carcinoma (ccRCC) expresses the highest levels of CD70 among all solid tumors. Despite the important clinical efficacy of immunotherapy by anti-PD-1 in RCC patients, the overall response to anti-PD1 remains modest. The relationship between the CD27-CD70 interaction in the RCC and the response to immunotherapy is still unclear.Materials and Methods
To study the CD27 and CD70 expression in the tumor microenvironment (TME), FFPE tumor tissues from 25 RCC patients were analysed using multiplex in situ immunofluorescence. 10 fresh RCC tumor samples were collected to analyse the phenotype of CD27+ T cells by flow cytometry and 4 samples were proceeded for single-cell RNA-seq analysis. A cohort of metastatic RCC patients (n = 35) treated by anti-PD-1 were enrolled for the measurement of plasma sCD27 by ELISA and the survival analysis is also realized.Results
In the TME, we demonstrated that CD27+ T cells interact with CD70-expressing tumor cells. In fresh tumors from RCC patients, CD27+ T cells express higher levels of cleaved caspase 3 (a classical marker of apoptosis) than CD27- T cells. We confirmed the apoptotic signature (BAX, FASLG, BCL2L11, CYCS, FBXO32, LGALS1, PIK3R1, TERF1, TXNIP, CDKN2A) of CD27+ T cells by single-cell RNAseq analysis. CD27+T cells also had a tissue resident memory T cell phenotype with enriched gene expression of ITGAE, PRDM1, RBPJ and ZNF683. Moreover, CD27+T cells display an exhaustion phenotype with the expression of multiple inhibitory receptors gene signature (PDCD1, CTLA4, HAVCR2, LAG3, etc). Besides, intratumoral CD27-CD70 interaction significantly correlates with plasma sCD27 concentration in RCC (p = 0.0017). In metastatic RCC patients treated with anti-PD-1, higher levels of sCD27 predict poor overall survival (p = 0.037), while it did not correlate with inflammatory markers or clinical prognostic criteria.Conclusions
In conclusion, we demonstrated that sCD27, a surrogate of T cell dysfunction in tumors likely induced by persistent interactions of CD27+T cells and CD70-expressing tumor cells, is a predictive biomarker of resistance to immunotherapy in mRCC. To our knowledge, this is the first report showing that a peripheral blood biomarker may reflect certain aspects of the tumor-host interaction in the tumor microenvironment. Given the frequent expression of CD70 and CD27 in solid tumors, our findings may be further extended to other types of tumors. CD70-CD27 interaction could thus be considered as a mechanism of tumor escape, but also a novel therapeutic target in cancers.Disclosure Information
N. Benhamouda: None. I. Sam: None. N. Epaillard: None. A. Gey: None. A. Saldmann: None. J. Pineau: None. M. Hasan: None. V. Verkarre: None. V. Libri: None. S. Mella: None. C. Granier: None. C. Broudin: None. P. Ravel: None. B. Jabla: None. N. Chaput: None. L. Albiges: None. Y. Vano: None. O. Adotevi: None. S. Oudard: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; SIRIC CARPEM, FONCER. E. Tartour: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; Fondation ARC, INCA PLBio, Labex Immuno-Oncology, SIRIC CARPEM, FONCER, IDEX université de Paris, Inserm Transfert.Keywords:
Cancer Immunotherapy
Tumor Antigen
This collection contains 10 reports published In Frontiers in Oncology between August 2020 and March 2022 broadly focused on the immunobiology of renal cell carcinoma (RCC), the impact of immunotherapy in the setting of RCC, and the identification of biomarkers that are prognostic of RCC patient outcomes and response to immunotherapy.
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Metastatic renal cell carcinoma (RCC) usually resistants to traditional chemotherapy and radiotherapy.Interleukin-2 and interferon-αare the common significant cytokines studied extensively.However the clinical efficacy is not desirable when interleukin-2 or interferon-αis used alone.With the development of molecular immunology,studies on vaccines and autologous cytokine induced killer Cells progress quickly.This review summarizes the research progression of immunotherapy for metastatic renal cell carcinoma.
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Metastatic renal cell carcinoma; Immunotherapy
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Bone metastases or local recurrences are widely viewed as poor prognostic signs for successful immunotherapy for metastatic renal cell carcinoma (RCC), and even partial remission is a rarity. We assessed the efficacy of the combination of radio and chemo-immunotherapy for bone metastases or local recurrences form RCC.From February 1994 until September 1997 twelve patients with progressive renal cell carcinoma (9 with bone metastases and 3 with local recurrence) were treated with a combination of chemo-immunotherapy and radio therapy.Four out of twelve patients achieved complete remission (CR), one patient had a partial remission (PR), three were stable and four had disease progression under radio therapy and chemo-immunotherapy. Yet three pts. died of the disease. The toxicity symptoms according to WHO ranged between grade 2 and grade 3.Our data suggest that the combination of radio therapy and chemo-immunotherapy may induce a synergistic antitumor effect for the treatment of bone metastases or local recurrences from renal cell carcinoma.
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As a common tumor of the urinary system, the morbidity and mortality related to renal carcinoma, are increasing annually. Clear cell renal cell carcinoma (CCRCC) is the most common subtype of renal cell carcinoma, accounting for approximately 75% of the total number of patients with renal cell carcinoma. Currently, the clinical treatment of ccRCC involves targeted therapy, immunotherapy, and a combination of the two. In immunotherapy, PD-1/PD-L1 blocking of activated T cells to kill cancer cells is the most common treatment. However, as treatment progresses, some patients gradually develop resistance to immunotherapy. Meanwhile, other patients experience great side effects after immunotherapy, resulting in a survival status far lower than the expected survival rate. Based on these clinical problems, many researchers have been working on the improvement of tumor immunotherapy in recent years and have accumulated numerous research results. We hope to find a more suitable direction for future immunotherapy for ccRCC by combining these results and the latest research progress.
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