CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma

Sharma, Padmanee; Shen, Yu; Wen, Sijin; Yamada, Sachiko; Jungbluth, Achim A.; Gnjatic, Sacha; Bajorin, Dean F.; Reuter, Victor E.; Herr, Harry W.; Old, Lloyd J.; Satô, Eiichi

doi:10.1073/pnas.0611618104

Cited by 456 publications

(351 citation statements)

References 22 publications

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“…A high number of tumor-infiltrating CD8 1 T lymphocytes were observed as a favorable prognostic factor for survival in some studies of human cancers, including endometrial cancer, 32 ovarian cancer, 8 colorectal cancer, 33 esophageal cancer 34 and urothelial carcinoma. 35 Other studies on non-small cell lung cancer, 36 anal squamous cell carcinoma 24 and renal cell carcinoma 37 reported that CD8 1 T lymphocytes were a negative prognostic factor. The CD8 1 T-cell subpopulation has been considered to be the effector in the antitumor response; however, when the status of activation was explored, most of the cells were underprimed (CD45RO 1 ) 38 or inactivated (in this study, the GrB/CD8 ratio was 7/48), regardless of the effector/target ratio within the tumor tissue (data not shown).…”

Section: Comparative Numbers Of Cd4mentioning

confidence: 98%

A reversed CD4/CD8 ratio of tumor-infiltrating lymphocytes and a high percentage of CD4+FOXP3+ regulatory T cells are significantly associated with clinical outcome in squamous cell carcinoma of the cervix

et al. 2010

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In this study, 40 biopsy samples collected from cervical cancer patients at the First Affiliated Hospital of Xi'an Jiaotong University, China, were retrospectively assessed using immunohistochemistry for CD4 1 and CD8 1 tumor-infiltrating lymphocytes (TILs) and were analyzed for the expression of FOXP3, OX40, granzyme B (GrB) and perforin (Prf). The proliferating index of the TILs was determined by assessing Ki67 expression. We determined the prognostic value of low and high numbers of TILs on survival by performing KaplanMeier analysis using median values as the cut-off points. Except for the number of CD4 1 FOXP3 1 regulatory T cells (Tregs) and the CD4/ CD8 ratio, none of the CD4 1 , CD8 1 , OX40 1 , GrB 1 or Prf 1 TILs were associated with the overall 5-year survival rate. The 5-year survival rate was significantly lower in patients who had a high percentage of Tregs as compared with the those who had a lower percentage (35.3% versus 88.9%, P50.001), while the 5-year survival rate was significantly higher in patients with a high CD4/CD8 ratio as compared with patients who had a low CD4/CD8 ratio (82.4% versus 44.4%, P50.029). When we considered the deaths and surviving cases as separate groups, we found that both the number of CD4 1 T cells and the CD4/CD8 ratio were significantly lower in patients who died as compared with those who survived (26.33611.80 versus 47.79638.18, P50.023 and 0.6060.25 versus 1.1761.02, P50.019, respectively). In conclusion, decreased proportions of tumor-infiltrating CD4 1 T cells with high percentages of Tregs and reversed CD4/CD8 ratios were significantly associated with the clinical outcome of patients with cervical carcinoma.

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Section: Comparative Numbers Of Cd4mentioning

confidence: 98%

A reversed CD4/CD8 ratio of tumor-infiltrating lymphocytes and a high percentage of CD4+FOXP3+ regulatory T cells are significantly associated with clinical outcome in squamous cell carcinoma of the cervix

et al. 2010

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“…The presence of CD8 + TIL is associated with improved survival in patients with muscle invasive urothelial carcinoma while the frequency of immunosuppressive regulatory T cells and macrophages correlates with reduced survival. 9 Tumors characterized by high CD4 + T cells, low regulatory T cells, and low CD68 + or CD163 + macrophages are associated with prolonged recurrence free survival in patients that responded to BCG therapy. 10 Thus, while the profile of anti-tumor and pro-tumor immune subsets in bladder cancer are predictive of clinical outcomes, the presence of TIL alone is not associated with the suppression of tumor growth.…”

Section: Introductionmentioning

confidence: 99%

Expansion of tumor infiltrating lymphocytes (TIL) from bladder cancer

et al. 2018

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Advanced bladder cancer patients have limited therapeutic options resulting in a median overall survival (OS) between 12 and 15 months. Adoptive cell therapy (ACT) using tumor infiltrating lymphocytes (TIL) has been used successfully in treating patients with metastatic melanoma, resulting in a median OS of 52 months. In this study, we investigated the feasibility of expanding TIL from the tumors of bladder cancer patients. Primary bladder tumors and lymph node (LN) metastases were collected. Tumor specimens were minced into fragments, placed in individual wells of a 24-well plate, and propagated in high dose IL-2 for four weeks. Expanded TIL were phenotyped by flow cytometry and anti-tumor reactivity was assessed after co-culture with autologous tumor digest and IFN-gamma ELISA. Of the 28 transitional cell bladder or LN tumors collected, 14/20 (70%) primary tumors and all of the LN metastases demonstrated TIL expansion. Expanded TIL were predominantly CD3+ (median 63%, range 10–87%) with a median of 30% CD8 + T cells (range 5–70%). TIL secreted IFN-gamma in response to autologous tumor. Addition of agonisitic 4-1BB antibody improved TIL expansion from primary bladder tumors regardless of pre-treatment with chemotherapy. This study establishes the practical first step towards an autologous TIL therapy process for therapeutic testing in patients with bladder cancer.

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“…Results from numerous studies on diverse human cancers have suggested that the infiltration of tumor-reactive T cells, especially CD8 þ T cells, strongly correlates with tumor regression and better prognosis (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). However, endogenous tumor-reactive T cells are usually present in low numbers and often become anergic, likely due to the immunosuppressive environment in the tumor sites.…”

Section: Introductionmentioning

confidence: 99%

Cytomegalovirus-Based Vaccine Expressing a Modified Tumor Antigen Induces Potent Tumor-Specific CD8+ T-cell Response and Protects Mice from Melanoma

Qiu

Huang

Grenier

et al. 2015

Cancer Immunology Research

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The presence of tumor-infiltrating CD8 þ T cells is associated with tumor regression and better prognosis. Cytomegalovirus (CMV) infection elicits a robust and long-lasting CD8 þ T-cell response, which makes CMV a potentially promising vaccine vector against cancer. In the current study, we used recombinant murine CMV (MCMV) strains as prophylactic and therapeutic vaccines in an aggressive B16 lung metastatic melanoma model. Immunization with MCMV-expressing ovalbumin (OVA) induced a potent OVA-specific CD8 þ T-cell response and was effective in protecting mice from OVAexpressing B16 melanoma in an antigen-dependent manner. We engineered MCMV to express a modified B16 melanoma antigen gp100 (MCMV-gp100KGP). Immunization with MCMV-gp100KGP was highly effective in overcoming immune tolerance to self-antigen and induced a strong, long-lasting gp100-specific CD8 þ T-cell response even in the presence of preexisting anti-CMV immunity. Furthermore, both prophylactic and therapeutic vaccinations of mice with MCMV-gp100KGP effectively protected mice from highly aggressive lung B16-F10 melanoma, and the protection was mediated by gp100-specific CD8 þ T cells. We showed that MCMV is a superior vaccine vector compared with a commonly used vesicular stomatitis virus vector. Collectively, our studies demonstrate that CMV is a promising vaccine vector to prevent and treat tumors.

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CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma

Cited by 456 publications

References 22 publications

A reversed CD4/CD8 ratio of tumor-infiltrating lymphocytes and a high percentage of CD4+FOXP3+ regulatory T cells are significantly associated with clinical outcome in squamous cell carcinoma of the cervix

A reversed CD4/CD8 ratio of tumor-infiltrating lymphocytes and a high percentage of CD4+FOXP3+ regulatory T cells are significantly associated with clinical outcome in squamous cell carcinoma of the cervix

Expansion of tumor infiltrating lymphocytes (TIL) from bladder cancer

Cytomegalovirus-Based Vaccine Expressing a Modified Tumor Antigen Induces Potent Tumor-Specific CD8+ T-cell Response and Protects Mice from Melanoma

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