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Inability of ovarian cancers to upregulate their MHC-class I surface expression marks their aggressiveness and increased susceptibility to NK cell-mediated cytotoxicity

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Abstract

We extended our previous observations with other tumor models to study seven ovarian tumor cell lines—OVCAR3, OVCAR4, OVCAR8, SKOV3, Kuramochi, OAW28, and CaOV3. We found that NK cells targeted and killed poorly differentiated OVCAR8 and CAOV3; these two tumor lines express lower MHC-class I and higher CD44 surface receptors. OVCAR3 and OVCAR4 were more resistant to NK cell-mediated cytotoxicity, and SKOV3, Kuramochi and OAW28 had intermediate sensitivity to NK cell-mediated cytotoxicity, likely representing well-differentiated and moderately differentiated ovarian tumor cell lines, respectively. Similar trends were observed for secretion of IFN-γ by the NK cells when co-cultured with different ovarian tumor cell lines. Treatment with both IFN-γ and TNF-α upregulated MHC-class I in all ovarian tumor cell lines and resulted in tumor resistance to NK cell-mediated cytotoxicity and decreased secretion of IFN-γ in co-cultures of NK cells with tumors cells with the exception of OVCAR8 and CAOV3 which did not upregulate MHC-class I and remained sensitive to NK cell-mediated cytotoxicity and increased secretion of IFN-γ when co-cultured with NK cells. Similarly, treatment with NK cell supernatants induced resistance to NK cell-mediated cytotoxicity in OVCAR4 but not in OVCAR8, and the resistance to killing was correlated with the increased surface expression of MHC-class I in OVCAR4 but not in OVCAR8. In addition, OVCAR4 was found to be carboplatin sensitive before and after treatment with IFN-γ and NK cell supernatants, whereas OVCAR8 remained carboplatin resistant with and without treatment with IFN-γ and NK cell supernatants. Overall, sensitivity to NK cell-mediated killing correlated with the levels of tumor differentiation and aggressiveness, and more importantly, poorly differentiated ovarian tumors were unable to upregulate MHC-class I under the activating conditions for MHC-class I, a feature that was not seen in other tumor models and may likely be specific to ovarian tumors. Such tumors may also pose a significant challenge in elimination by the T cells; however, NK cells are capable of targeting such tumors and can be exploited to eliminate these tumors in immunotherapeutic strategies.

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Acknowledgements

The authors are grateful to funding agencies and donors for supporting the work.

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Author notes

  1. Nishant Chovatiya, Kawaljit Kaur, Sara Huerta-Yepez, and Po-Chun Chen have contributed equally to this work.

Authors and Affiliations

  1. Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave., Los Angeles, 90095, USA

    Nishant Chovatiya, Kawaljit Kaur, Sara Huerta-Yepez, Po-Chun Chen & Anahid Jewett

  2. The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, 10833 Le Conte Ave., Los Angeles, CA, 90095, USA

    Sanaz Memarzadeh & Anahid Jewett

  3. Department of Obstetrics and Gynecology, UCLA David Geffen School of Medicine, University of California Los Angeles, 610 Charles E Young Drive East, 3018 Terasaki Life Sciences Building, Los Angeles, CA, 90095, USA

    Adam Neal, Gabriella DiBernardo & Sanaz Memarzadeh

  4. UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, 90095, USA

    Adam Neal, Gabriella DiBernardo & Sanaz Memarzadeh

  5. Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA, 90095, USA

    Sanaz Memarzadeh

  6. The VA Greater Los Angeles Healthcare System, Los Angeles, CA, 90073, USA

    Sanaz Memarzadeh

  7. Seraph Research Institute, 4142 Lankershim Blvd, Toluca Lake, CA, 91602, USA

    Serhat Gumrukcu

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Contributions

NC, SHY, and PCC generated data, reviewed, and edited the article. KK analyzed data, prepared figures, wrote, reviewed, and edited the article. NA and GD provided tumor samples and technical help. SG reviewed and edited the paper. AJ and SM oversaw the studies, conceptualization of the article, reviewed and edited the article, and acquired funding.

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Correspondence to Sanaz Memarzadeh or Anahid Jewett.

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Chovatiya, N., Kaur, K., Huerta-Yepez, S. et al. Inability of ovarian cancers to upregulate their MHC-class I surface expression marks their aggressiveness and increased susceptibility to NK cell-mediated cytotoxicity. Cancer Immunol Immunother 71, 2929–2941 (2022). https://doi.org/10.1007/s00262-022-03192-7

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