Interrelationships and clinical significance of expression of immunological markers in invasive breast carcinoma

Oldford, Sharon A. (2006) Interrelationships and clinical significance of expression of immunological markers in invasive breast carcinoma. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

The immunologic and prognostic significance of tumor cell HLA class II expression and immune cell infiltration in invasive breast carcinoma is unclear. The studies described in this thesis involved investigating several hypotheses regarding the anti-tumor immune response in invasive breast carcinoma in an attempt to provide clarification. -- We postulated that the significance of tumor cell HLA-DR expression is dependent on HLA-DRB allotypes. In a pilot study, HLA-DR+ tumor cells differentially expressed HLA-DRβ allotypes, with DRβ1*04 preferentially expressed. An expanded study with clinicopathological arid outcome data, confirmed these findings and demonstrated HLA-Dβ1*04 and HLA-DRβ1*13 expression by breast tumor cells, oppositely associate with survival. Evaluation of the intratumoral cytokine milieu suggested prognostic differences were attributable to variation in immune responsiveness, as HLA-DRβ1*04+ tumors had elevated TH1-type cytokines, while DRβ1*13 expressing tumors had elevated immunoregulatory markers. In non-DRB1*04 tumors, lack of expression of one or more HLA-DRβ allotypes by HLA-DR+ tumors independently predicted decreased survival time, suggesting it may function in immune evasion. -- Since in vitro studies demonstrated HLA-DR+ tumor cells function as antigen presenting cells, we evaluated the role of co-expression of the HLA class II co-chaperones, Ii and HLA-DM. DR+Ii+DM+ breast tumor cells independently predicted improved survival while DR+Ii+DM- tumors predicted decreased survival. Determination of intratumoral cytokine levels indicated improved prognosis of patients with DR+Ii+DM+ tumors was attributable to enhanced TH1-type immunity and elevated IFN-γ associated with improved survival. -- As infiltrating inflammatory cells constitute the major source of immune-modulating cytokines, we correlated infiltrating cell subsets with cytokine mRNA levels. We observed the prognostic significance of tumor infiltrating cells is dependent on the balance of pro-inflammatory and immunoregulatory cytokines. A small exploratory study investigating whether genetic variation in cytokine genes partially regulate intratumoral cytokine responses demonstrated that allelic variation in cytokine gene regulatory sequences play a minor role controlling cytokine levels in breast tumors. -- This expanded characterization of the in situ immune response m breast carcinoma enhances the understanding of anti-tumor immunity. This study suggests that future attempts to design and implement immunotherapeutic strategies in breast carcinoma patients should consider HLA-DRB allotypes, and involve co-incident enhancement of cell mediated immunity and suppression of immunoregulatory mechanisms.

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