# Insufficient Expression of the Autophagic Protein ATG16L1 Results in Accelerated Carcinogenesis Related to an Aberrant B Cell Response

## TL;DR

Reduced ATG16L1 protein leads to faster cancer development in the colon and mouth, possibly due to abnormal B cell activity.

## Contribution

This study reveals a novel role of ATG16L1 in cancer progression through its impact on B cell function and cytokine balance.

## Key findings

- ATG16L1HM mice showed increased susceptibility to colon and oral cancer compared to wild-type mice.
- Altered cytokine levels and elevated B cell counts in ATG16L1HM mice correlate with accelerated carcinogenesis.
- Lower IgG levels in ATG16L1HM mice suggest impaired immune response despite increased B cell numbers.

## Abstract

Autophagy‐related proteins (ATGs) regulate a great variety of cellular responses beyond autophagy. In cancer, the role of ATG proteins is central, as evidenced in spontaneous cancer emerging in animals lacking ATG proteins.

To determine whether ATG16L1 may be participating in tumorigenesis in colonic and oral mucosa and its likely association with adaptive immune cell deregulation (e.g., B cells).

Wild‐type (WT) and ATG16L1 hypomorphic mice (ATG16L1HM) were induced with colitis‐associated colon cancer (CAC) by delivering azoxymethane (AOM) and dextran sodium sulfate (DSS), whereas oral cancer was generated by administering 4‐nitroquinoline‐1‐oxide (4NQO) in tap water. Tissue samples were collected and the histopathological damage was assessed. Also, secondary lymphoid organs (i.e., spleen and draining lymph nodes) were assayed for cytokine output and lymphocyte distribution by means of flow cytometry, and IgG levels were assayed in plasma samples.

ATG16L1HM animals turned out to be more susceptible to colon and oral carcinogenesis than WT mice. In CAC, WT mice preserved colon length and presented individual colonic tumors, whereas ATG16L1HM mice presented shortened colons and tumor masses. Likewise, WT mice exhibited oral leukoplakia (pre‐neoplastic lesions), whereas ATG16L1HM mice showed tumors. The greater susceptibility observed in ATG16L1HM animals was associated with imbalanced cytokine production (increased IL‐4 levels and lower IL‐15 output) and higher numbers of B cells in secondary lymphoid organs. This latter was also found under steady conditions, and despite having more B cells, cancer‐induced ATG16L1HM mice presented lower levels of total circulating IgG.

Suboptimal expression of the autophagic protein ATG16L1 results in accelerated carcinogenesis, and an altered B cell response may be one of the aggravating factors.