Spontaneous Mammary Tumors Differ Widely in Their Inherent Sensitivity to Adoptively Transferred T Cells

Abstract

Immunotherapy of cancer can lead to the selection of antigen loss variants, which provides strong rationale to target oncogenes that are essential for tumor growth or viability. To investigate this concept, we tagged the HER2/neu oncogene with epitopes from ovalbumin to confer recognition by T-cell receptor transgenic CD8 + (OT-I) and CD4 + (OT-II) T cells. Transgenic mice expressing neu OT-I/OT-II developed mammary adenocarcinomas at 6 to 10 months of age. Adoptively transferred naive OT-I cells (with or without OT-II cells) proliferated vigorously on encountering neu OT-I/OT-II -expressing tumors. This was followed by the complete regression of 37% of tumors, whereas others showed partial/stable responses (40%) or progressive disease (23%). Those tumors undergoing complete regression never recurred. In mice with multiple primary tumors, simultaneous regressions and nonregressions were often seen, indicating that immune evasion occurred at a local rather than systemic level. The majority of nonregressing tumors expressed Neu OT-I/OT-II and MHC class I, and many avoided rejection through a profound block to T-cell infiltration. Thus, T cells directed against an essential oncogene can permanently eradicate a subset of spontaneous, established mammary tumors. However, in other tumors, local barriers severely limit the therapeutic response. To maximize the efficacy of immunotherapy against spontaneous cancers, predictive strategies that take into account the heterogeneity of the tumor microenvironment will be required. [Cancer Res 2007;67(13):6442-50]

CD8+ T Cells Induce Complete Regression of Advanced Ovarian Cancers by an Interleukin (IL)-2/IL-15–Dependent Mechanism

“…To study T-cell responses to ovarian tumors in immunocompetent mice, we used a previously described strategy, in which CD4 + and CD8 + T-cell epitopes from the model antigen ovalbumin were attached to the COOH terminus of rat neu to generate a fusion protein designated Neu OT-I/OT-II (36). An expression vector containing the neu OT-I/OT-II cDNA was transfected into the ovarian tumor cell line ID8 (37).…”

“…Because ID8 cells are already transformed, they do not require neu OT-I/OT-II for tumorigenesis. Hence, the WT allele of neu was used instead of the activated allele described previously (36). Although not essential for tumor formation, Neu nevertheless served as a convenient, traceable, and physiologically relevant carrier protein for the ovalbumin epitopes.…”

“…We have previously described transgenic mice that express Neu OT-I/OT-II in the mammary epithelium under the control of the MMTV promoter for use as a model of spontaneous breast cancer (36). Because MMTV/neu OT-I/OT-II mice are tolerant to the Neu OT-I/OT-II protein and do not develop mammary tumors until >12 months of age, we reasoned that at a younger age they could serve as hosts for Neu OT-I/OT-II -expressing ID8-G7 cells.…”

Cancer vaccines: Uses of HLA transgenic mice compared to genetically modified mice

“…Recently, Wall e. al. (38) modified the MMTV/neu model to express at the end of the rat neu gene the dominant class-I and a class-II epitopes derived from ovalbumin. These mice were further engineered and expressed then also a dominant-negative mutant of p53 (DNp53, R172H) under the control of the whey acid protein (WAP) promoter in order to accelerate tumor formation.…”

Age-dependent tolerance to an endogenous tumor-associated antigen

“…The influence of antigen-specific tolerance varies depending on the number and source of T cells [8,9]. Examination of transferred cognate transgenic T cells into tumor-bearing hosts has determined the conditions for optimal effector function and may have general clinical applications [reviewed in [10]], but the function of a diverse T cell repertoire differs from that of a T cell clone [11].…”