Lung cancer is the most common cause of cancer related death in the world. Approximately 80% to 90% of cases involve Non–Small-Cell Lung Cancer (NSCLC), which includes adenocarcinoma and squamous cell carcinoma. As many as 30% of patients with stage I disease experience recurrence after surgery. The correlation between tumor-infiltrating immune cells and the prognosis of patients with lung cancer is controversial. A tumor is composed of malignant, stromal, endothelial, and immune cells that form a heterogeneous network and exhibit complex interactions. Spontaneous tumor regressions occurring concomitantly with autoimmune manifestations and the higher incidence of tumors in immunosuppressed patients are indications of the involvement of the immune system in tumor rejection. Mice deficient in immune functions spontaneously develop tumors. The density of tumor-infiltrating lymphocytes (TILs) with cytotoxic and memory phenotypes is highly predictive of good clinical outcome in many solid tumors.
It is now well established that immune responses can take place at distance of secondary lymphoid organs, in “tertiary lymphoid structures” (TLS) or “Tertiary Lymphoid Organ” (TLO). These lymph node-like structures can develop in lung cancer patients. They have been initially named “Tumor-induced Bronchus-Associated Lymphoid Tissues” (Ti-BALT) as they were never found in the non-tumoral tissues of NSCLC patients. The density of mature DC, a population which was selectively detected in TLS, is associated with a favorable clinical outcome in patients with early-stage NSCLC and in metastatic stage suggesting that lung cancer-associated TLS represent an activation site for tumor-specific T cells.
Furthermore, a high density of B cells in TLS (named “TLS-B cells” or “Follicular B cells”) correlates with long-term survival of patients with early-stage and advanced-stage NSCLC, in accordance with ongoing humoral immune response in TLS. The combination of TLS-B cells and TLS-mature DC allowed the identification of NSCLC patients with the best clinical outcome. The presence of TLS has been reported in other human tumors including, but not limited to, colorectal, breast cancer and melanoma, indicating that ectopic TLS arise in many solid tumors.
Thus, the present inventions relates to methods for predicting the survival time of patients suffering from a lung cancer using TLS and cell density as biomarkers of cancer prognosis. In particular, they relate to use as biomarkers of:
- the cell density of follicular B cells present in tumor-induced lymphoid structures in a tumor tissue sample;
- the cell density of CD8+ cells and DC-LAMP+ dendritic cells present in a tumor tissue sample;
- the cell density of regulatory T (Treg) cells, and the cell density of one further population of immune cells selected from the group consisting of TLS-mature DC or TLS-B cells or Tconv cells, CD8+ T cells or CD8+ Granzyme-B+ T cells in said tumor tissue sample obtained from the subject.
Scientific Publication(s):
Am J Respir Crit Care Med., 2014 April 1, Germain C. et al., Presence of B cells in tertiary lymphoid structures is associated with a protective immunity in patients with lung cancer, doi: 10.1164
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Cancer Res., 2014 February 1, Goc J. et al., Dendritic cells in tumor-associated tertiary lymphoid structures signal a Th1 cytotoxic immune contexture and license the positive prognostic value of infiltrating CD8+ T cells, doi: 10.1158/0008-5472.CAN-13-1342