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Focused antibody response in plasma cell-infiltrated non-medullary (NOS) breast cancers

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Abstract

Breast tumors with prominent plasma cell (PC) infiltrates often have a more favorable natural course that may plausibly be mediated by anti-tumor activity of the elicited antibodies. These breast tumor-associated PCs are typically IgG dominant in contrast to normal breast PCs, which are mainly IgA. It is our hypothesis that this PC infiltration represents a host immune response that is driven by one or more tumor antigens. Previously, we and others showed that medullary carcinoma (MC) had a focused repertoire and features suggestive of a protein antigen driven response. Infrequently, non-MC, not otherwise specified (NOS) breast tumors may exhibit heavy PC infiltrations, also of IgG isotype. In this first characterization of this favorable prognosis NOS subgroup, IgG heavy chain (Hc) and light chain (Lc) variable (V) regions from three PC-infiltrated NOS tumors were randomly cloned and sequenced. We found biased (V) gene usage by the infiltrating PCs and somatic hypermutation in the rearranged Ig Hc and Lc V regions that were compatible with antigenic selection of the progenitor B cells. The antibody response of NOS infiltrated breast cancer is repertoire-focused, with 13–68% of isolates being clonally reiterated in the samples. Each NOS patient used distinct Hc V-D-J and Lc V-J rearrangements, with her own immune response “footprint,” but the overall pattern of gene usage followed that typical of exogenous antigen-induced immune responses. The data are consistent with the hypothesis that PC infiltrates infrequently arising in NOS tumors, as previously inferred for MC, are in response to one or more breast cancer-associated protein tumor antigens.

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Notes

  1. Ridolfi et al [2] reviewed 10-year death rates for 28 NOS patients whose tumors had high PC-infiltration (25% dead, 7/28) that were lower than an equal number of NOS patients with lower PC levels (46% dead, 13/28) (p = 0.08; Fisher exact test), for a reduced overall risk ratio of 0.54 for high PC-infiltration. This comparison is seen to be better powered for a strong conclusion with a larger control sample size: a contemporaneous unselected series of 251 NOS patients from the same institution (MSKCC) with 42% dead (risk ratio 0.60 favoring PC-infiltrated), that is borderline significant at p = 0.057, unadjusted for the included fraction with high PC infiltrates. (Removing a favorable PC-infiltrated fraction from the control group would be expected to increase the control death rate and strengthen the p value, but these further patients were not so evaluated.) Comparison of high PC-infiltrates with a pool of these two control groups (risk ratio 0.58) yields a p = 0.051 for death reduction. Analogously, in the “atypical” medullary group, death with many PCs (18%, 10/54) was significantly lower than with few PCs (44%, 11/25) (p < 0.01), for a favorable risk ratio of 0.41 for high PC-infiltration [2]. (Because the hypothesis is that non-MC tumors enjoy benefit from PC infiltration that parallels the improved survival in MC, a single-tailed test is employed.) In an earlier study of 135 cases of NOS tumors with PC-infiltrates, Berg and Robbins similarly cited a reduction in death rates of better than 50% [27]. The reduction was described as “significant”, but statistical tests were not reported. However, a p < 0.05 is likely for this comparison when considering the larger sample sizes and the comparable or better cited risk reductions. Thus, independent studies support the legitimacy and interest of this defined PC-infiltrated subgroup of NOS breast cancers. Additional such evaluations would be valuable future topics for research.

  2. A configuration for the library of IgG VH paired with mainly IgA-derived VL in the latter (NOS) study [39] could reduce the native, specific VH-VL components of the library for authentic antigen recognition, but it would not diminish the possibility to select for irrelevant antigens, if such were occurring.

  3. Interestingly, this B repertoire focus contrasts with the infiltrating T lymphocytes from the same tumors that are not repertoire restricted [44].

Abbreviations

PC:

Plasma cell

MC:

Medullary carcinoma

NOS:

Not otherwise specified

Ig:

Immunoglobulin

Hc:

Heavy chain

Lc:

Light chain

Fab:

Fragment antigen-binding

RT-PCR:

Reverse transcription-polymerase chain reaction

V:

Variable minigene or variable region (VJ or VDJ)

D:

Diversity minigene

J:

Joining minigene

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Acknowledgments

We gratefully acknowledge Dr Louis Weiner for availing to this study the excellent resources of the Fox Chase Cancer Center Tumor Bank Facility. We also thank Dr A Ebralidze and Dr Q Ma for technical advice. This work was supported by grants to R. P. J. from the National Cancer Institute/NIH and the Massachusetts Department of Public Health.

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Authors and Affiliations

  1. Biotherapeutics Development Lab, Harvard Institute of Human Genetics, Harvard Medical School and Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA

    Y. Wang, F. Ylera, M. Boston, S. -G. Kang & R. P. Junghans

  2. Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, 02115, USA

    J. L. Kutok

  3. Experimental Histopathology Service, Fox Chase Cancer Center, 7701 Burholme Ave, Philadelphia, PA, 19111, USA

    A. J. P. Klein-Szanto

  4. Division of Surgical Research, Boston University School of Medicine, Roger Williams Medical Center, 825 Chalkstone Avenue, Providence, RI, 02908, USA

    R. P. Junghans

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  1. Y. Wang
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  3. M. Boston
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Correspondence to R. P. Junghans.

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Wang, Y., Ylera, F., Boston, M. et al. Focused antibody response in plasma cell-infiltrated non-medullary (NOS) breast cancers. Breast Cancer Res Treat 104, 129–144 (2007). https://doi.org/10.1007/s10549-006-9409-3

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