Tumor-associated antigen expressing listeria monocytogenes induces effective primary and memory T-cell responses against hepatic colorectal cancer metastases

Kelly Olino, Satoshi Wada, Barish H. Edil, Xiaoyu Pan, Kristen Meckel, Walter Weber, Jill Slansky, Koji Tamada, Peter Lauer, Dirk Brockstedt, Drew Pardoll, Richard Schulick, Kiyoshi Yoshimura

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Purpose: Despite advances in therapy for the treatment of metastatic colorectal cancer, many patients die of hepatic disease. Current immunotherapeutic strategies are likely limited by inhibitory signals from the tumor. To successfully eliminate tumor deposits within an organ, an appropriate immunologic milieu to amplify antitumor responses must be developed. Methods: We used a murine model utilizing the CT26 colon cancer cell line to analyze primary and memory tumor-specific T-cell responses induced by an attenuated actin A and internalin B deleted immunodominant tumor-associated antigen expressing strain of Listeria monocytogenes for the treatment of metastatic colorectal cancer. Results: Treatment of mice bearing established hepatic metastases with this L. monocytogenes strain led to the generation of a strong initial tumor-specific cytotoxic CD8+ T-cell response that successfully treated 90% of animals. Tumor antigen-specific central and effector memory T cells were also generated and protected against tumor rechallenge. These cell populations, when measured before and after tumor rechallenge, showed a marked expansion of antigen-specific effector CD8+ effector memory T cells. This strain of L. monocytogenes was able to down-modulate the expression of the immune checkpoint molecule, PD-1, within the tumor microenvironment but had variable effects on CTLA-4 expression. Conclusions: This L. monocytogenes strain generated a highly effective antitumor T-cell response, providing a basis for the development of this vaccine platform in patients with liver metastases.

Original languageEnglish (US)
JournalAnnals of Surgical Oncology
Volume19
Issue numberSUPPL. 3
DOIs
StatePublished - Jul 2012
Externally publishedYes

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Listeria monocytogenes
Neoplasm Antigens
Liver Neoplasms
Colorectal Neoplasms
Neoplasm Metastasis
T-Lymphocytes
Neoplasms
Liver
Immunodominant Epitopes
Tumor Microenvironment
Therapeutics
Colonic Neoplasms
Actins
Vaccines
Antigens
Cell Line
Population

ASJC Scopus subject areas

  • Surgery
  • Oncology

Cite this

Tumor-associated antigen expressing listeria monocytogenes induces effective primary and memory T-cell responses against hepatic colorectal cancer metastases. / Olino, Kelly; Wada, Satoshi; Edil, Barish H.; Pan, Xiaoyu; Meckel, Kristen; Weber, Walter; Slansky, Jill; Tamada, Koji; Lauer, Peter; Brockstedt, Dirk; Pardoll, Drew; Schulick, Richard; Yoshimura, Kiyoshi.

In: Annals of Surgical Oncology, Vol. 19, No. SUPPL. 3, 07.2012.

Research output: Contribution to journalArticle

Olino, K, Wada, S, Edil, BH, Pan, X, Meckel, K, Weber, W, Slansky, J, Tamada, K, Lauer, P, Brockstedt, D, Pardoll, D, Schulick, R & Yoshimura, K 2012, 'Tumor-associated antigen expressing listeria monocytogenes induces effective primary and memory T-cell responses against hepatic colorectal cancer metastases', Annals of Surgical Oncology, vol. 19, no. SUPPL. 3. https://doi.org/10.1245/s10434-011-2037-0
Olino, Kelly ; Wada, Satoshi ; Edil, Barish H. ; Pan, Xiaoyu ; Meckel, Kristen ; Weber, Walter ; Slansky, Jill ; Tamada, Koji ; Lauer, Peter ; Brockstedt, Dirk ; Pardoll, Drew ; Schulick, Richard ; Yoshimura, Kiyoshi. / Tumor-associated antigen expressing listeria monocytogenes induces effective primary and memory T-cell responses against hepatic colorectal cancer metastases. In: Annals of Surgical Oncology. 2012 ; Vol. 19, No. SUPPL. 3.
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AU - Meckel, Kristen

AU - Weber, Walter

AU - Slansky, Jill

AU - Tamada, Koji

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AB - Purpose: Despite advances in therapy for the treatment of metastatic colorectal cancer, many patients die of hepatic disease. Current immunotherapeutic strategies are likely limited by inhibitory signals from the tumor. To successfully eliminate tumor deposits within an organ, an appropriate immunologic milieu to amplify antitumor responses must be developed. Methods: We used a murine model utilizing the CT26 colon cancer cell line to analyze primary and memory tumor-specific T-cell responses induced by an attenuated actin A and internalin B deleted immunodominant tumor-associated antigen expressing strain of Listeria monocytogenes for the treatment of metastatic colorectal cancer. Results: Treatment of mice bearing established hepatic metastases with this L. monocytogenes strain led to the generation of a strong initial tumor-specific cytotoxic CD8+ T-cell response that successfully treated 90% of animals. Tumor antigen-specific central and effector memory T cells were also generated and protected against tumor rechallenge. These cell populations, when measured before and after tumor rechallenge, showed a marked expansion of antigen-specific effector CD8+ effector memory T cells. This strain of L. monocytogenes was able to down-modulate the expression of the immune checkpoint molecule, PD-1, within the tumor microenvironment but had variable effects on CTLA-4 expression. Conclusions: This L. monocytogenes strain generated a highly effective antitumor T-cell response, providing a basis for the development of this vaccine platform in patients with liver metastases.

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