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Endogenous tumor-reactive CD8(+) T cells are differentiated effector cells expressing high levels of CD11a and PD-1 but are unable to control tumor growth.

Liu X, Gibbons RM, Harrington SM, Krco CJ, Markovic SN, Kwon ED, Dong H - Oncoimmunology (2013)

Bottom Line: In order to optimize therapeutic protocols and monitor the effectiveness of such therapies, reliable biomarkers are needed.In the peripheral blood of melanoma patients, tumor antigen-specific CD8(+) T cells were associated with a population of CD11a(high) CD8(+) T cells that co-expressed high levels of PD-1.Increased CD11a(high)CD8(+) T cells and delayed tumor growth were observed in PD-1 deficient mice, suggesting that the antitumor effector functions of CD8(+) T cells is compromised by an elevated expression of PD-1.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology; College of Medicine; Mayo Clinic; Rochester, MN USA.

ABSTRACT
Immunotherapies aimed at enhancing natural or endogenous antitumor T-cell immunity in patients affected by advanced malignancies are currently being implemented in the clinic with promising results. In order to optimize therapeutic protocols and monitor the effectiveness of such therapies, reliable biomarkers are needed. We used CD11a, an integrin that is upregulated on the surface of effector and memory CD8(+) T cells, and PD-1, an immunoregulatory receptor expressed by activated T cells, as biomarkers to identify, quantify and monitor endogenous tumor-reactive cytotoxic T lymphocytes (CTLs) in two mouse tumor models and in the peripheral blood of 12 patients affected by Stage IV melanoma. High expression levels of CD11a and PD-1 were detected among CD8(+) T cells residing within primary and metastatic murine tumor sites, as well as in spontaneous murine breast cancer tissues. In the peripheral blood of melanoma patients, tumor antigen-specific CD8(+) T cells were associated with a population of CD11a(high) CD8(+) T cells that co-expressed high levels of PD-1. Healthy donors exhibited a comparatively much lower frequency of such PD-1(+)CD11a(high)CD8(+) T cells. Phenotypic analyses demonstrated that CD11a(high)CD8(+) T cells are proliferating (Ki67(+)) and activated (CD62L(-)CD69(+)). Increased CD11a(high)CD8(+) T cells and delayed tumor growth were observed in PD-1 deficient mice, suggesting that the antitumor effector functions of CD8(+) T cells is compromised by an elevated expression of PD-1. The CD11a(high)CD8(+) T-cell population expresses high levels of PD-1 and presumably constitutes the cellular target of PD-1 blockade therapy. The expression level of CD11a and PD-1 by CD8(+) T cells may therefore represent a novel biomarker to identify and monitor endogenous tumor-reactive CTLs. This may not only provide an immunological readout for evaluating the efficacy of immunotherapy but also contribute to the selection of cancer patients who are likely to benefit from anti-PD-1 therapy.

No MeSH data available.


Related in: MedlinePlus

Figure 8. PD-1+CD11ahighCD8+ T cells are increased in the peripheral blood of melanoma patients. (A–D) Peripheral blood mononuclear cells (PBMCs) were isolated from healthy donors or patients affected by Stage IV melanoma. (A) Tumor antigen specificity of the CD11ahighCD8+ T cells found among the PBMCs of melanoma patients. The percentage of MART-1-tet+ cells among CD11ahigh and CD11alowCD8+ T cells is reported. (B) Percentages of MART-1-tet+CD11ahigh and MART-1-tet+CD11alow cells among total CD8+ T cells (means ± SEM, n = 10). (C) Expression of PD-1 and CTLA-4 by CD11ahigh and CD11alowCD8+ T cells found among the PBMCs of melanoma patients. (D) Frequency of PD-1+CD11ahigh cells among total CD8+ T cells in the PBMCs of healthy donors (n = 6) and melanoma patients (n = 12).
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Figure 8: Figure 8. PD-1+CD11ahighCD8+ T cells are increased in the peripheral blood of melanoma patients. (A–D) Peripheral blood mononuclear cells (PBMCs) were isolated from healthy donors or patients affected by Stage IV melanoma. (A) Tumor antigen specificity of the CD11ahighCD8+ T cells found among the PBMCs of melanoma patients. The percentage of MART-1-tet+ cells among CD11ahigh and CD11alowCD8+ T cells is reported. (B) Percentages of MART-1-tet+CD11ahigh and MART-1-tet+CD11alow cells among total CD8+ T cells (means ± SEM, n = 10). (C) Expression of PD-1 and CTLA-4 by CD11ahigh and CD11alowCD8+ T cells found among the PBMCs of melanoma patients. (D) Frequency of PD-1+CD11ahigh cells among total CD8+ T cells in the PBMCs of healthy donors (n = 6) and melanoma patients (n = 12).

Mentions: To test whether CD11ahighCD8+ T cells represent tumor-specific CD8+ T cells in cancer patients, we analyzed CD8+ T cells from the peripheral blood of 10 patients affected by Stage IV melanoma. We used the HLA-A2/MART-1 tetramer (MART-1-tet) to define tumor-specific CD8+ T cells. The CD11ahigh subset of CD8+ T cells contained a significantly higher frequency of MART-1-tet+ T cells as compared with the CD11alowCD8+ subset (p = 0.001, Fig. 8A and B), suggesting that CD11ahighCD8+ T cells represent tumor-specific CD8+ T cells. The CD11ahighCD8+ T-cell compartment of these patients expressed elevated levels of PD-1 (but not of the other prominent immunoregulatory receptor CTLA-4) compared with CD11alowCD8+ T cells (Fig. 8C). The frequency of PD-1+CD11ahighCD8+ T cells was significantly increased in the peripheral blood of the cancer patients (18.7 ± 1.8%) as compared with healthy donors (1.7 ± 0.4%, p < 0.0001, Fig. 8D). When we used a CD11a antibody that specifically recognizes a unique epitope of CD11a implicated in the activation of LFA-1 complex (MEM-83), we identified a similarly increased population of PD-1+CD11ahighCD8+ T cells in these melanoma patients (data not shown), suggesting that this population of CD8+ T cells is TAA-primed. Our results suggest that most tumor-specific CD8+ T cells of advanced melanoma patients are CD11ahighCD8+ T cells that co-express elevated levels of PD-1, presumably accounting for the dysfunctional state of tumor-reactive CD8+ T cells that normally characterizes these patients.


Endogenous tumor-reactive CD8(+) T cells are differentiated effector cells expressing high levels of CD11a and PD-1 but are unable to control tumor growth.

Liu X, Gibbons RM, Harrington SM, Krco CJ, Markovic SN, Kwon ED, Dong H - Oncoimmunology (2013)

Figure 8. PD-1+CD11ahighCD8+ T cells are increased in the peripheral blood of melanoma patients. (A–D) Peripheral blood mononuclear cells (PBMCs) were isolated from healthy donors or patients affected by Stage IV melanoma. (A) Tumor antigen specificity of the CD11ahighCD8+ T cells found among the PBMCs of melanoma patients. The percentage of MART-1-tet+ cells among CD11ahigh and CD11alowCD8+ T cells is reported. (B) Percentages of MART-1-tet+CD11ahigh and MART-1-tet+CD11alow cells among total CD8+ T cells (means ± SEM, n = 10). (C) Expression of PD-1 and CTLA-4 by CD11ahigh and CD11alowCD8+ T cells found among the PBMCs of melanoma patients. (D) Frequency of PD-1+CD11ahigh cells among total CD8+ T cells in the PBMCs of healthy donors (n = 6) and melanoma patients (n = 12).
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Figure 8: Figure 8. PD-1+CD11ahighCD8+ T cells are increased in the peripheral blood of melanoma patients. (A–D) Peripheral blood mononuclear cells (PBMCs) were isolated from healthy donors or patients affected by Stage IV melanoma. (A) Tumor antigen specificity of the CD11ahighCD8+ T cells found among the PBMCs of melanoma patients. The percentage of MART-1-tet+ cells among CD11ahigh and CD11alowCD8+ T cells is reported. (B) Percentages of MART-1-tet+CD11ahigh and MART-1-tet+CD11alow cells among total CD8+ T cells (means ± SEM, n = 10). (C) Expression of PD-1 and CTLA-4 by CD11ahigh and CD11alowCD8+ T cells found among the PBMCs of melanoma patients. (D) Frequency of PD-1+CD11ahigh cells among total CD8+ T cells in the PBMCs of healthy donors (n = 6) and melanoma patients (n = 12).
Mentions: To test whether CD11ahighCD8+ T cells represent tumor-specific CD8+ T cells in cancer patients, we analyzed CD8+ T cells from the peripheral blood of 10 patients affected by Stage IV melanoma. We used the HLA-A2/MART-1 tetramer (MART-1-tet) to define tumor-specific CD8+ T cells. The CD11ahigh subset of CD8+ T cells contained a significantly higher frequency of MART-1-tet+ T cells as compared with the CD11alowCD8+ subset (p = 0.001, Fig. 8A and B), suggesting that CD11ahighCD8+ T cells represent tumor-specific CD8+ T cells. The CD11ahighCD8+ T-cell compartment of these patients expressed elevated levels of PD-1 (but not of the other prominent immunoregulatory receptor CTLA-4) compared with CD11alowCD8+ T cells (Fig. 8C). The frequency of PD-1+CD11ahighCD8+ T cells was significantly increased in the peripheral blood of the cancer patients (18.7 ± 1.8%) as compared with healthy donors (1.7 ± 0.4%, p < 0.0001, Fig. 8D). When we used a CD11a antibody that specifically recognizes a unique epitope of CD11a implicated in the activation of LFA-1 complex (MEM-83), we identified a similarly increased population of PD-1+CD11ahighCD8+ T cells in these melanoma patients (data not shown), suggesting that this population of CD8+ T cells is TAA-primed. Our results suggest that most tumor-specific CD8+ T cells of advanced melanoma patients are CD11ahighCD8+ T cells that co-express elevated levels of PD-1, presumably accounting for the dysfunctional state of tumor-reactive CD8+ T cells that normally characterizes these patients.

Bottom Line: In order to optimize therapeutic protocols and monitor the effectiveness of such therapies, reliable biomarkers are needed.In the peripheral blood of melanoma patients, tumor antigen-specific CD8(+) T cells were associated with a population of CD11a(high) CD8(+) T cells that co-expressed high levels of PD-1.Increased CD11a(high)CD8(+) T cells and delayed tumor growth were observed in PD-1 deficient mice, suggesting that the antitumor effector functions of CD8(+) T cells is compromised by an elevated expression of PD-1.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology; College of Medicine; Mayo Clinic; Rochester, MN USA.

ABSTRACT
Immunotherapies aimed at enhancing natural or endogenous antitumor T-cell immunity in patients affected by advanced malignancies are currently being implemented in the clinic with promising results. In order to optimize therapeutic protocols and monitor the effectiveness of such therapies, reliable biomarkers are needed. We used CD11a, an integrin that is upregulated on the surface of effector and memory CD8(+) T cells, and PD-1, an immunoregulatory receptor expressed by activated T cells, as biomarkers to identify, quantify and monitor endogenous tumor-reactive cytotoxic T lymphocytes (CTLs) in two mouse tumor models and in the peripheral blood of 12 patients affected by Stage IV melanoma. High expression levels of CD11a and PD-1 were detected among CD8(+) T cells residing within primary and metastatic murine tumor sites, as well as in spontaneous murine breast cancer tissues. In the peripheral blood of melanoma patients, tumor antigen-specific CD8(+) T cells were associated with a population of CD11a(high) CD8(+) T cells that co-expressed high levels of PD-1. Healthy donors exhibited a comparatively much lower frequency of such PD-1(+)CD11a(high)CD8(+) T cells. Phenotypic analyses demonstrated that CD11a(high)CD8(+) T cells are proliferating (Ki67(+)) and activated (CD62L(-)CD69(+)). Increased CD11a(high)CD8(+) T cells and delayed tumor growth were observed in PD-1 deficient mice, suggesting that the antitumor effector functions of CD8(+) T cells is compromised by an elevated expression of PD-1. The CD11a(high)CD8(+) T-cell population expresses high levels of PD-1 and presumably constitutes the cellular target of PD-1 blockade therapy. The expression level of CD11a and PD-1 by CD8(+) T cells may therefore represent a novel biomarker to identify and monitor endogenous tumor-reactive CTLs. This may not only provide an immunological readout for evaluating the efficacy of immunotherapy but also contribute to the selection of cancer patients who are likely to benefit from anti-PD-1 therapy.

No MeSH data available.


Related in: MedlinePlus