Survival in rectal cancer is predicted by T cell infiltration of tumour-associated lymphoid nodules

Abstract

SummaryLymphoid nodules are a normal component of the mucosa of the rectum, but little is known about their function and whether they contribute to the host immune response in malignancy. In rectal cancer specimens from patients with local (n = 18), regional (n = 12) and distant (n = 10) disease, we quantified T cell (CD3, CD25) and dendritic cell (CD1a, CD83) levels at the tumour margin as well as within tumour-associated lymphoid nodules. In normal tissue CD3+ , but not CD25 + , T cells are concentrated at high levels within lymphoid nodules, with significantly fewer cells found in surrounding normal mucosa (P = 0·001). Mature (CD83), but not immature (CD1a), dendritic cells in normal tissue are also found clustered almost exclusively within lymphoid nodules (P = < 0·0001). In rectal tumours, both CD3+ T cells (P = 0·004) and CD83+ dendritic cells (P = 0·0001) are also localized preferentially within tumour-associated lymphoid nodules. However, when comparing tumour specimens to normal rectal tissue, the average density of CD3 + T cells (P = 0·0005) and CD83+ dendritic cells (P = 0·0006) in tumourassociated lymphoid nodules was significantly less than that seen in lymphoid nodules in normal mucosa. Interestingly, regardless of where quantified, T cell and dendritic cell levels did not depend upon the stage of disease. Increased CD3 + T cell infiltration of tumour-associated lymphoid nodules predicted improved survival, independent of stage (P = 0·05). Other T cell (CD25) markers and different levels of CD1a + or CD83 + dendritic cells did not predict survival. Tumour-associated lymphoid nodules, enriched in dendritic cells and T cells, may be an important site for antigen presentation and increased T cell infiltration may be a marker for improved survival.

Immune Contexture, Immunoscore, and Malignant Cell Molecular Subgroups for Prognostic and Theranostic Classifications of Cancers

“…Their link with clinical prognosis has been reported in a variety of human solid tumors. The majority of these studies report that an extensive infiltration with DC is associated with increased OS and cover many tumors types, including melanoma (Gerber et al, 2014;Ladányi et al, 2007;Neagu et al, 2013;Simonetti et al, 2007), HCC (Cai et al, 2006;Yin et al, 2003), gallbladder (Furihata et al, 2005;Nakakubo et al, 2003), oral (Reichert et al, 2001), esophageal (Furihata et al, 1992;Ishigami et al, 2003a;Lu et al, 2013), gastric (Amoueian et al, 2015Ananiev et al, 2011;Kashimura et al, 2012;Tsukayama et al, 2005), NSCLC (Al-Shibli et al, 2009;Dai et al, 2010;Hald et al, 2013;Inoshima et al, 2002;Johnson et al, 2000), colorectal (Gulubova et al, 2012;McMullen et al, 2010;Nakayama et al, 2003;Väyrynen et al, 2014), bladder (Inoue et al, 1993), breast (Iwamoto et al, 2003;La Rocca et al, 2008;Lespagnard et al, 1999;Park et al, 2012), endometrial (Honig et al, 2005;Lijun et al, 2012), and ovarian cancer (Eisenthal et al, 2001;Zhang et al, 2015). Nevertheless, the infiltration with CD123 + plasmacytoid DC has been associated with shorter OS in breast cancer ( Jensen et al, 2012;Treilleux et al, 2004), as well as the presence of CD208 + and CD1a + DCs in colorectal (Sandel et al, 2005)...…”

Tertiary lymphoid structures in cancer and beyond

“…It can be difficult to determine if the lymphoid aggregates described in these studies are bona fide TLS (see Box 1) or simply an area hosting a dense lymphoid infiltration. In humans, the presence of intratumoral organized lymphoid aggregates has been reported in colorectal and rectal cancer [44][45][46][47][48][49], breast cancer [48,[50][51][52][53][54][55], melanoma [37,48,[56][57][58], MALT lymphoma [25,26], ovarian cancer [48,59], germ cell tumors [60], and NSCLC [38][39][40]42,48,61,62]. Interestingly, these structures can be observed at all stages of the disease, comprising metastases …”

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

“…In this context, it is therefore surprising that ELFs arise in tumours at all. However, ELFs have been described in numerous cancers including colorectal,60, 88 rectal,89 breast,67, 90, 91 ovarian67, 92 and germ cell93 cancers, as well as melanoma,62, 67, 94 mucosal‐associated lymphoid tissue lymphoma39 and non‐small cell lung carcinoma95, 96 (NSCLC; see Dieu‐Nosjean et al . for a comprehensive review of ELFs in cancer9).…”