Intertumoral heterogeneity of CD3þ and CD8þ T-cell densities in the microenvironment of DNA mismatch-repair–deficient colon cancers: Implications for prognosis

Harry H Yoon, Qian D Shi, Erica N. Heying, Andrea Muranyi, Joerg Bredno, Faith Ough, Azita Djalilvand, June Clements, Rebecca Bowermaster, Wen Wei Liu, Michael Barnes, Steven Robert Alberts, Kandavel Shanmugam, Frank A Sinicrope

Research output: Contribution to journalArticle

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Abstract

Purpose: Colorectal cancers with deficient DNA mismatch repair (dMMR) are presumed to uniformly have dense lymphocytic infiltration that underlies their favorable prognosis and is critical to their responsiveness to immunotherapy, as compared with MMR-proficient (pMMR) tumors. We examined T-cell densities and their potential heterogeneity in a large cohort of dMMR tumors. Experimental Design: CD3þ and CD8þ T-cell densities were quantified at the invasive margin (IM) and tumor core (CT) in 561 stage III colon cancers (dMMR, n ¼ 278; pMMR, n ¼ 283) from a phase III adjuvant trial (N0147). Their association with overall survival (OS) was determined using multivariable Cox analysis. Results: Although CD3þ and CD8þ T-cell densities in the tumor microenvironment were higher in dMMR versus pMMR tumors overall, intertumoral heterogeneity in densities between tumors was significantly higher by 30% to 88% among dMMR versus pMMR cancers (P < 0.0001 for all four T-cell subtypes [CD3þIM, CD3þCT, CD8þIM, CD8þCT]). A substantial proportion of dMMR tumors (26% to 35% depending on the T-cell subtype) exhibited T-cell densities as low as that in the bottom half of pMMR tumors. All four T-cell subtypes were prognostic in dMMR with CD3þIM being the most strongly prognostic. Low (vs. high) CD3þIM was independently associated with poorer OS among dMMR (HR, 4.76; 95% confidence interval, 1.43–15.87; P ¼ 0.0019) and pMMR tumors (P ¼ 0.0103). Conclusions: Tumor-infiltrating T-cell densities exhibited greater intertumoral heterogeneity among dMMR than pMMR colon cancers, with CD3þIM providing robust stratification of both dMMR and pMMR tumors for prognosis. Potentially, lower T-cell densities among dMMR tumors may contribute to immunotherapy resistance.

Original languageEnglish (US)
Pages (from-to)125-133
Number of pages9
JournalClinical Cancer Research
Volume25
Issue number1
DOIs
StatePublished - Jan 1 2019

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DNA Mismatch Repair
Colonic Neoplasms
Cell Count
T-Lymphocytes
DNA
Neoplasms
Immunotherapy
DNA Repair-Deficiency Disorders
Tumor Microenvironment
Colorectal Neoplasms
Research Design
Confidence Intervals

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Intertumoral heterogeneity of CD3þ and CD8þ T-cell densities in the microenvironment of DNA mismatch-repair–deficient colon cancers : Implications for prognosis. / Yoon, Harry H; Shi, Qian D; Heying, Erica N.; Muranyi, Andrea; Bredno, Joerg; Ough, Faith; Djalilvand, Azita; Clements, June; Bowermaster, Rebecca; Liu, Wen Wei; Barnes, Michael; Alberts, Steven Robert; Shanmugam, Kandavel; Sinicrope, Frank A.

In: Clinical Cancer Research, Vol. 25, No. 1, 01.01.2019, p. 125-133.

Research output: Contribution to journalArticle

Yoon, Harry H ; Shi, Qian D ; Heying, Erica N. ; Muranyi, Andrea ; Bredno, Joerg ; Ough, Faith ; Djalilvand, Azita ; Clements, June ; Bowermaster, Rebecca ; Liu, Wen Wei ; Barnes, Michael ; Alberts, Steven Robert ; Shanmugam, Kandavel ; Sinicrope, Frank A. / Intertumoral heterogeneity of CD3þ and CD8þ T-cell densities in the microenvironment of DNA mismatch-repair–deficient colon cancers : Implications for prognosis. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 1. pp. 125-133.
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abstract = "Purpose: Colorectal cancers with deficient DNA mismatch repair (dMMR) are presumed to uniformly have dense lymphocytic infiltration that underlies their favorable prognosis and is critical to their responsiveness to immunotherapy, as compared with MMR-proficient (pMMR) tumors. We examined T-cell densities and their potential heterogeneity in a large cohort of dMMR tumors. Experimental Design: CD3{\th} and CD8{\th} T-cell densities were quantified at the invasive margin (IM) and tumor core (CT) in 561 stage III colon cancers (dMMR, n ¼ 278; pMMR, n ¼ 283) from a phase III adjuvant trial (N0147). Their association with overall survival (OS) was determined using multivariable Cox analysis. Results: Although CD3{\th} and CD8{\th} T-cell densities in the tumor microenvironment were higher in dMMR versus pMMR tumors overall, intertumoral heterogeneity in densities between tumors was significantly higher by 30{\%} to 88{\%} among dMMR versus pMMR cancers (P < 0.0001 for all four T-cell subtypes [CD3{\th}IM, CD3{\th}CT, CD8{\th}IM, CD8{\th}CT]). A substantial proportion of dMMR tumors (26{\%} to 35{\%} depending on the T-cell subtype) exhibited T-cell densities as low as that in the bottom half of pMMR tumors. All four T-cell subtypes were prognostic in dMMR with CD3{\th}IM being the most strongly prognostic. Low (vs. high) CD3{\th}IM was independently associated with poorer OS among dMMR (HR, 4.76; 95{\%} confidence interval, 1.43–15.87; P ¼ 0.0019) and pMMR tumors (P ¼ 0.0103). Conclusions: Tumor-infiltrating T-cell densities exhibited greater intertumoral heterogeneity among dMMR than pMMR colon cancers, with CD3{\th}IM providing robust stratification of both dMMR and pMMR tumors for prognosis. Potentially, lower T-cell densities among dMMR tumors may contribute to immunotherapy resistance.",
author = "Yoon, {Harry H} and Shi, {Qian D} and Heying, {Erica N.} and Andrea Muranyi and Joerg Bredno and Faith Ough and Azita Djalilvand and June Clements and Rebecca Bowermaster and Liu, {Wen Wei} and Michael Barnes and Alberts, {Steven Robert} and Kandavel Shanmugam and Sinicrope, {Frank A}",
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T1 - Intertumoral heterogeneity of CD3þ and CD8þ T-cell densities in the microenvironment of DNA mismatch-repair–deficient colon cancers

T2 - Implications for prognosis

AU - Yoon, Harry H

AU - Shi, Qian D

AU - Heying, Erica N.

AU - Muranyi, Andrea

AU - Bredno, Joerg

AU - Ough, Faith

AU - Djalilvand, Azita

AU - Clements, June

AU - Bowermaster, Rebecca

AU - Liu, Wen Wei

AU - Barnes, Michael

AU - Alberts, Steven Robert

AU - Shanmugam, Kandavel

AU - Sinicrope, Frank A

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Purpose: Colorectal cancers with deficient DNA mismatch repair (dMMR) are presumed to uniformly have dense lymphocytic infiltration that underlies their favorable prognosis and is critical to their responsiveness to immunotherapy, as compared with MMR-proficient (pMMR) tumors. We examined T-cell densities and their potential heterogeneity in a large cohort of dMMR tumors. Experimental Design: CD3þ and CD8þ T-cell densities were quantified at the invasive margin (IM) and tumor core (CT) in 561 stage III colon cancers (dMMR, n ¼ 278; pMMR, n ¼ 283) from a phase III adjuvant trial (N0147). Their association with overall survival (OS) was determined using multivariable Cox analysis. Results: Although CD3þ and CD8þ T-cell densities in the tumor microenvironment were higher in dMMR versus pMMR tumors overall, intertumoral heterogeneity in densities between tumors was significantly higher by 30% to 88% among dMMR versus pMMR cancers (P < 0.0001 for all four T-cell subtypes [CD3þIM, CD3þCT, CD8þIM, CD8þCT]). A substantial proportion of dMMR tumors (26% to 35% depending on the T-cell subtype) exhibited T-cell densities as low as that in the bottom half of pMMR tumors. All four T-cell subtypes were prognostic in dMMR with CD3þIM being the most strongly prognostic. Low (vs. high) CD3þIM was independently associated with poorer OS among dMMR (HR, 4.76; 95% confidence interval, 1.43–15.87; P ¼ 0.0019) and pMMR tumors (P ¼ 0.0103). Conclusions: Tumor-infiltrating T-cell densities exhibited greater intertumoral heterogeneity among dMMR than pMMR colon cancers, with CD3þIM providing robust stratification of both dMMR and pMMR tumors for prognosis. Potentially, lower T-cell densities among dMMR tumors may contribute to immunotherapy resistance.

AB - Purpose: Colorectal cancers with deficient DNA mismatch repair (dMMR) are presumed to uniformly have dense lymphocytic infiltration that underlies their favorable prognosis and is critical to their responsiveness to immunotherapy, as compared with MMR-proficient (pMMR) tumors. We examined T-cell densities and their potential heterogeneity in a large cohort of dMMR tumors. Experimental Design: CD3þ and CD8þ T-cell densities were quantified at the invasive margin (IM) and tumor core (CT) in 561 stage III colon cancers (dMMR, n ¼ 278; pMMR, n ¼ 283) from a phase III adjuvant trial (N0147). Their association with overall survival (OS) was determined using multivariable Cox analysis. Results: Although CD3þ and CD8þ T-cell densities in the tumor microenvironment were higher in dMMR versus pMMR tumors overall, intertumoral heterogeneity in densities between tumors was significantly higher by 30% to 88% among dMMR versus pMMR cancers (P < 0.0001 for all four T-cell subtypes [CD3þIM, CD3þCT, CD8þIM, CD8þCT]). A substantial proportion of dMMR tumors (26% to 35% depending on the T-cell subtype) exhibited T-cell densities as low as that in the bottom half of pMMR tumors. All four T-cell subtypes were prognostic in dMMR with CD3þIM being the most strongly prognostic. Low (vs. high) CD3þIM was independently associated with poorer OS among dMMR (HR, 4.76; 95% confidence interval, 1.43–15.87; P ¼ 0.0019) and pMMR tumors (P ¼ 0.0103). Conclusions: Tumor-infiltrating T-cell densities exhibited greater intertumoral heterogeneity among dMMR than pMMR colon cancers, with CD3þIM providing robust stratification of both dMMR and pMMR tumors for prognosis. Potentially, lower T-cell densities among dMMR tumors may contribute to immunotherapy resistance.

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