Immune microenvironment linked to prognosis of follicular lymphoma

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A dual approach to B cells is needed

The findings of the study by Dr. Kiaii and his colleagues are particularly important as novel T-cell–mediated therapies are being developed for B-cell malignancies.

Lymphoma cells often induce immune tolerance by deleting or inactivating tumor-specific T cells. One attempt at overcoming this phenomenon has been chimeric antigen receptor (CAR) therapy; however, best results have been restricted to patients who had a low tumor burden and received cytotoxic chemotherapy beforehand.

Dr. Stephen Ansell

The chemotherapy administered was likely to have not only depleted malignant cells but also decreased immunosuppressive cells. ... Malignant B cells, and the immunosuppressive tumor microenvironment they promote, may therefore remain a barrier to effective adoptive immunotherapy in B-cell lymphoma, particularly in patients with chemotherapy-resistant, bulky disease.

The data presented confirm that malignant B cells promote a profoundly immunosuppressive microenvironment and thereby protect themselves from being targeted by the immune system.

Future therapies in follicular lymphoma, including immunotherapies such as CAR T cells, will need to not only deplete malignant B cells but also inhibit the immunosuppressive mechanisms by which malignant B cells suppress the antitumor immune response. A dual approach that both depletes malignant cells and promotes immune function may subsequently result in a better clinical outcome for patients with follicular lymphoma.

Dr. Stephen M. Ansell is professor of medicine at the Mayo Clinic in Rochester, Minn. He made his remarks in an accompanying editorial (J. Clin. Oncol. 2013;31:2641-2). Dr. Ansell disclosed having no relevant conflicts of interest.



Tumor-induced genetic changes in the immune cells of lymph nodes predict outcomes in patients with follicular lymphoma, according to a study published in the Journal of Clinical Oncology.

Investigators performed gene expression profiling of tumor-infiltrating T cells (TILs) from lymph node biopsies at diagnosis in 172 treatment-naive patients with follicular lymphoma and of T cells from reactive tonsils and peripheral blood of 12 healthy donors.

Compared with the T cells from healthy donors, the TILs had marked upregulation of several genes and downregulation of others, as well as impaired motility. Moreover, similar changes could be induced in healthy T cells by exposing them to lymphoma cells, said Dr. Shahryar Kiaii of the Institute of Cancer and Barts and the London School of Medicine and Dentistry and his associates.

The numbers and locations within the lymph nodes of the TILs showing altered gene expression predicted both overall survival and the time to transformation to B-cell lymphoma – sometimes dramatically. Certain combinations were associated with 70%-80% reductions in the risks of these outcomes.

"These results contribute to our understanding of the complex interactions of lymphoma cells, TILs, and macrophages in their microenvironment and help us generate hypotheses. But until we have a better understanding of these interactions, it does not yet seem feasible to incorporate [immunohistochemistry] analysis of TILs in [follicular lymphoma] for prognosis," the investigators wrote.

"However, because nonmalignant infiltrating immune cells play a crucial role in outcomes in [follicular lymphoma], understanding the nature and impact of the abnormalities induced in TILs in these patients is vital before any immunotherapeutic strategies can be implemented to alter the immune microenvironment in [follicular lymphoma]," they added.

In the study, the investigators constructed tissue microarrays and used mRNA expression profiles, real-time polymerase chain reaction assays, and immunohistochemistry to assess gene expression in highly purified CD4 and CD8 T cells.

Results showed that the TILs had an abnormal gene expression profile when compared with the healthy T cells, Dr. Kiaii and his associates said (J. Clin. Oncol. 2013;31:2654-61).

The genes showing the greatest upregulation were those for pro-melanin–concentrating hormone (PMCH); ETS translocation variant 1 (ETV1); and tumor necrosis factor receptor superfamily, member 9 (TNFRSF9).

One of the genes showing greatest downregulation was the gene that encodes the cytoskeletal protein actinin (ACTN1), and the TILs indeed showed reduced motility when compared with the healthy T cells (P less than .025).

When cultured alone, healthy T cells did not express PMCH and had normal motility, but when cultured with follicular lymphoma cells, the T cells expressed this protein highly and had reduced motility (P = .0002).

The number of TILs expressing PMCH, ETV1, and NAMPT (nicotinamide phosphoribosyltransferase) and their locations in lymph nodes – in the malignant follicle (intrafollicular area), in the area between follicles (interfollicular area), and overall – as determined immunohistochemically, were significantly associated with both overall survival and time to transformation, the investigators said.

In multivariate analyses, the combination of the interfollicular-to-intrafollicular ratio of PMCH-expressing cells plus a high level of expression of NAMPT and a low level of expression of ETV1 in the intrafollicular area was the strongest predictor of longer time to transformation (hazard ratio, 0.19; P = .003).

Similarly, the combination of the number of PMCH- and NAMPT-expressing cells in the interfollicular area plus the interfollicular-to-intrafollicular ratio of ETV1 cells was the strongest predictor of better overall survival (hazard ratio, 0.32; P = .007).

The study was supported by grants from Cancer Research UK and the National Cancer Institute. One of the investigators disclosed receiving honoraria from Roche/Genentech and Celgene.

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